BrainImmune: Trends in Neuroendocrine Immunology http://www.brainimmune.com Expert views & state of art in neuroendocrine immunology & stress-immunity research by BrainImmune.com. Both fundamental & clinical aspects and their impacts on health & disease. Mon, 23 Apr 2018 17:57:09 +0000 en-US hourly 1 https://wordpress.org/?v=4.9.5 107933628 PNIRS and GEBIN Conference in 2019 in Berlin, Germany http://www.brainimmune.com/pnirs-gebin-conference-berlin/ Mon, 23 Apr 2018 17:50:41 +0000 http://www.brainimmune.com/?p=6161 The Psychoneuroimmunology Research Society (PNIRS) and the German Endocrine Brain Immune Network (GEBIN) will have their joint international meeting in Berlin, Germany, June 4-8, 2019. The meeting will take place at venues in/near the Charité, the famous University Hospital in Berlin. One location is the Lecture Hall Ruin (Hörsaalruine), which belongs to the Berlin Museum […]

The post PNIRS and GEBIN Conference in 2019 in Berlin, Germany appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
The Psychoneuroimmunology Research Society (PNIRS) and the German Endocrine Brain Immune Network (GEBIN) will have their joint international meeting in Berlin, Germany, June 4-8, 2019.

The meeting will take place at venues in/near the Charité, the famous University Hospital in Berlin.

PNIRS & GEBIN conference Berlin 1One location is the Lecture Hall Ruin (Hörsaalruine), which belongs to the Berlin Museum of Medical History.

The ruin of the former Rudolf Virchow Lecture Hall, with its historic charm, presents a unique event location that has made for an unforgettable experience for guests from all over the world.

The lecture hall was destroyed toward the end of World War II by bombings. Since the middle of the 1990s the “preserved” ruin has been used for formal events, social get-togethers and scientific exchange.

PNIRS & GEBIN conference Berlin 2The second location is the Langenbeck-Virchow-Haus, which is owned by the Berlin Medical Association and the German Surgery Association.

Built in 1913, it has a long history full of vicissitudes. For example, between 1945 and 1949, it was occupied by the Soviet military authority. In 1953, the first President of the German Democratic Republic, Wilhelm Pieck, was elected in the Great Hall of the Langenbeck-Virchow-Haus.

The two international societies, PNIRS & GEBIN, gather researchers of a number of scientific and medical disciplines including psychology, neurosciences, immunology, pharmacology, psychiatry, behavioral medicine, infectious diseases, endocrinology, dermatology and rheumatology, who are interested in interactions between the nervous system and the immune system, and the relationship between behavior and health.

The GEBIN makes the start on June 4-5 with the usual separation into sub-disciplines like “Peripheral Neuroimmune Interactions,” “Neuroendocrinology and Immune Function,” “Stress, Behavior, and Immune Function,” “Neuroimmunology & Neuroinfectiology in the CNS,” and finally “Neuroendocrine Immune Network in Psychiatric Disease.” GEBIN meets in the lecture hall ruin (Hörsaalruine).

This is followed by a common “Educational Short Course of PNIRS & GEBIN” on June 5, in the afternoon. The PNIRS meeting in the Langenbeck-Virchow-Haus goes through Saturday, June 8, with the “Featured Speaker Lecture,” the “Norman Cousins Lecture,” a Welcome Reception in the Natural History Museum Berlin, the “Bob Ader Lecture,” the “Frontiers in PNI Lecture, “ the “George Solomon Lecture,” and the Banquet Evening in Clärchens Ballhaus. In addition, several member-sponsored symposia will be presented.

See more: pnirs.org

The post PNIRS and GEBIN Conference in 2019 in Berlin, Germany appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
6161
Stress, Immune Function, and Health: The Connection http://www.brainimmune.com/stress-immune-function-health-book/ Mon, 23 Apr 2018 10:20:07 +0000 http://www.brainimmune.com/?p=6154 The ‘Stress, Immune Function, and Health: The Connection’ is written by Bruce S. Rabin, MD, PhD, a renowned physician-scientist and clinical immunologist. Dr. Rabin is professor of pathology and the director of the Division of Clinical Immunopathology, Department of Pathology at the University of Pittsburgh School of Medicine, US. Stress, Immune Function, and Health: The […]

The post Stress, Immune Function, and Health: The Connection appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
Stress Immune Function Health Bruce Rabin book amazonThe ‘Stress, Immune Function, and Health: The Connection’ is written by Bruce S. Rabin, MD, PhD, a renowned physician-scientist and clinical immunologist. Dr. Rabin is professor of pathology and the director of the Division of Clinical Immunopathology, Department of Pathology at the University of Pittsburgh School of Medicine, US.

Stress, Immune Function, and Health: The Connection is a single-author book, where Dr. Rabin provides his perspectives on brain- and stress-immune interactions, and how the activation of the central nervous system by stressful challenges influence the function of the immune system. The book represents an authoritative guide for physicians, scientists and for students in the fields of immunology, neuroscience and physiology.

The books provides an overview of the immune and nervous systems’ function and how these two major adaptive system are involved in functionally relevant cross-talk. In support of that interaction, research using animal models of stress has provided valuable information as to the effect of stress on basic immune function and susceptibility to infectious disease.

The books addresses issues such as stress and immunity, and different hormonal mechanisms of the central nervous system-immune system interactions. This includes the effects of the hypothalamic pituitary adrenal (HPA) axis and the peripheral autonomic nervous system, including the sympathetic nervous system. The author Bruce Rabin also demonstrates, in a concise, accessible manner, the ability of an individual’s immune system to alter susceptibility to immune-mediated diseases.

The book also deals with several key issues in this rapidly expanding field, including:

  • How distinct areas of the brain perceiving stressors challenges are able to communicate with the immune cells.
  • Psychological stress and stress-induced risks of disease development.
  • The effect on the immune system due to stress from an increased levels of different neurotransmitters, neuropeptides and hormones.
  • The issue of stress during pregnancy and its short and long-term effects.

Read more: Amazon

Related stories you may like:
Hans Selye and ‘The Stress of Life’ book
Hans Selye and the Birth of the Stress Concept
Selye and the 80th Birthday of Stress Research
Stress, Stress Hormones and the Immune System
David Goldstein, Adrenaline, the Inner World and the Scientific Integrative Medicine
Lena Johansson, Stress and Alzheimer’s Risk in Women
Stress and Cancer: A Link Through the Chinese Cultural Revolution
New Evidence That Psychological Stress Contributes To Peptic Ulcers Development

The post Stress, Immune Function, and Health: The Connection appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
6154
The Cross-talk between the Dopaminergic System and Innate Immunity: An Evolving Concept http://www.brainimmune.com/cross-talk-between-dopaminergic-system-and-innate-immunity/ Tue, 27 Mar 2018 19:45:16 +0000 http://www.brainimmune.com/?p=6058 Evolving Concept Dopamine (DA) is a well-known neurotransmitter in the central nervous system (CNS). An increasing body of evidence, however, indicates that DA is also an important communication mediator at the neural-immune interface [1-3]. Most research and studies to date have put the emphasis on DA and it’s regulation of adaptive immunity. Comparatively little is […]

The post The Cross-talk between the Dopaminergic System and Innate Immunity: An Evolving Concept appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
Evolving Concept

Dopamine (DA) is a well-known neurotransmitter in the central nervous system (CNS). An increasing body of evidence, however, indicates that DA is also an important communication mediator at the neural-immune interface [1-3].

Most research and studies to date have put the emphasis on DA and it’s regulation of adaptive immunity. Comparatively little is known about the role of DA in innate immunity, an area receiving much less attention despite some clear evidence that dopaminergic mechanisms affect key innate immune cells functions.

Here, we provide a brief overview of the current understanding and the recent data in this area. In addition, we also outline some new evidence suggesting a dysfunctional dopaminergic-immune system interface that may contribute to the development and progression of certain immune-mediated pathologies.

Sources and functions of dopamine

Cross-talk dopamine and innate immunity figure 1Dopamine, first identified in 1960 is synthesized from the amino acid tyrosine [4], in accordance with the pathway shown in Figure 1.

Figure 1. Dopamine synthesis.

In the CNS, DA is produced in different areas, such as substantia nigra, ventral tegmental area (VTA), amygdala, nucleus accumbens and the prefrontal cortex [5].

In the mammalian brain there are four major dopaminergic pathways: the nigrostriatal, mesolimbic, mesocortical, and tuberoinfundibolar (see Figure 2).

They are involved in the control of several key functions such as behavior, voluntary movement, feeding, attention, affect and motivation, pleasure and reward, drug addiction [6-11].

In the body’s periphery, DA plays important physiological roles in the regulation of the cardiovascular system and vascular tone, hormone secretion and gastrointestinal motility, and kidney functions, including the control of sodium homeostasis and the renin-angiotensin-aldosterone system [12,13].

Interestingly, the mesenteric organs, the gastrointestinal tract, spleen, and pancreas seem to produce close to half of the DA formed in the body [14].

In humans, the range of DA in the plasma is between 5.527 and 527 pmol/L [15]. Another study indicates that the concentration of DA is similar to those of epinephrine (adrenaline), 30 nmol/L. However, DA concentrations can increase in some particular conditions such as stress, or in the niche of a tumor.

Dopamine in human tissues can originate not only from endogenous biosynthetic pathways but also from many types of food and plants [16]. The most relevant issue regarding the food-related DA is that it cannot cross the blood brain barrier. Only one study of 1988 conducted in canines, highlighted that the absolute bioavailability of DA after oral administration is approximately 3% [17].

Cross-talk dopamine and innate immunity figure 2Figure 2. Brain dopaminergic pathways. 1) Mesolimbic and 2) mesocortical pathways control motivation, emotional response, desire, pleasure and reward; involved in the phenomena of addiction; determine delirium and hallucinations when hyperreactive. 3) Nigrostriatal pathway controls mostly the motor function. The degeneration of the cell bodies in this area is implicated in the genesis of Parkinson’s disease. 4) Tubero-infundibular pathway regulates the secretion of prolactin from the anterior pituitary gland. If dopamine cannot be released, then hyperprolactinemia is developed causing abnormal lactation and disruption of the menstrual cycle in women. Abbreviation: VTA, ventral tegmental area.

Dopaminergic receptors

The effect of DA is due to the interaction with two different receptor families that are tightly related, classes of 7-transmembrane, G-protein coupled receptors: D1-like (D1 DR and D5 DR, also known as D1a and D1b) and D2-like (D2 DR, D3 DR and D4 DR). D1-like receptors are located both on pre- and post-synaptic sites, whereas D2-like receptors are post-synaptic [19].

D1-like family receptors activate Gαs/olf proteins to stimulate cyclic adenosine monophosphate (cAMP) production by adenyl cyclase (AC), whereas D2-class receptors stimulate Gαi/o proteins, which inhibit AC, resulting in a drop of the levels of cAMP [20]. Despite DRs in the CNS are well characterized, their role and their characterization at the peripheral level is less known.

It is interesting to notice that there are two different isoforms of D2 DR: short (S) and long (L), generated by the alternative splicing of an exon [12]. These two variants of D2 receptor show not only functional differences, but also distinctive distribution in the brain: the D2L is mainly present on the neurons of striatum and nucleus accumbens, whereas the short form is in mesencephalon and hypothalamus [21].

Another important point regarding these receptors is the possibility that these have the form of heteromers with other dopaminergic receptors or with other classes of receptors [22]. The most well-known allosteric interaction between receptors is between the adenosine A2A receptor (A2AR) and DR D2 [23]. This heteromer has multiple and unique biochemical properties, and is responsible for the depressant effects of adenosine analogues and, conversely, for the psychostimulant effects of selective adenosine A2AR antagonists, and the non-selective antagonist (e.g. caffeine). It is also implicated in several neuropsychiatric disorders [24]. For several functions in the brain mediated by DA, there is a concomitant stimulation DR D1 and DR D2 which form a heteromer, not only in pathological conditions, but also under physiological conditions.

Regarding other DR heteromer we have only sporadic information; the D1-D3 DR was suggested to have therapeutic implications as a pharmacological target in Parkinson’s disease [25]. D2-D3 DR is considered as a target for antipsychotics [26] and the D2-D5 DR heteromer, similarly to D1-D2 DR, may have a role in calcium signaling, with the activation of CaMKII, involved in drug addiction and schizophrenia [27].

Dopaminergic regulation of the immune response: an overview

Dopamine is involved in the CNS-immune system interplay and immune cells themselves produce DA [28]. The effects of DA have been extensively studied on the adaptive immune response and in particular on T lymphocytes. The relevance of dopaminergic modulation of the adaptive immune response in disease conditions has been documented for multiple sclerosis (MS) [29, 30] and rheumatoid arthritis (RA) [31], and preliminary evidence has been recently provided for Parkinson’s disease (PD) [32].

The role of DA in the modulation of the innate immune response has received little attention and is not very well characterized.

Dopaminergic modulation of the innate immune system

Neutrophils are considered the first line of host defense from infectious pathogens, producing reactive oxygen species, neutrophil extracellular traps and cytokines, such as interleukin (IL)-8 [33]. Interestingly, recent data indicate that neutrophils can prolong their lifespan (more than the canonic few hours) to restore the condition of homeostasis [34].

As shown in the study of McKenna [35], all the five DR are present on the neutrophil surface, with D5 as the highest expressed, whereas D1 the lowest. Different in vitro studies evidenced an inhibitory role of DA on neutrophil functions. It was shown that DA exerts an inhibitory effect on some pivotal neutrophil functions such as superoxide anion production [36], adhesion molecules expression, cell migration and phagocytic activity [37- 39].

Cross-talk dopamine and innate immunity figure 3aFigure 3a and b.  Effects of dopamine on innate immune cells.

Moreover, DA is able to modify not only the functional aspects, but also the number of these cells. It was shown that in patients with Parkinson’s disease the count of neutrophils significantly decreased [40].  This is in agreement with what was observed by the group of Sookhai [41], which demonstrated that DA increases in vitro neutrophil apoptosis both in healthy subjects and in patients with systemic inflammatory response syndrome (see Figure 3).

Eosinophils make up about 1–3% of the white blood cells. IL-3, IL-5, and granulocyte macrophage colony stimulating factor (GM-CSF) are key cytokines that control eosinophil development, endothelial adhesion, activation and survival. These cells are considered end-stage cells involved in host protection against multicellular parasites. Along with mast cells and basophils, they also control mechanisms associated with allergy and asthma [42].

Cross-talk dopamine and innate immunity figure 3bEosinophils express on their surface all five DRs [35] but only few data are available about the effect of DA. The most relevant concept suggests that DA might be used as additional medication is that the administration of DA in patients awaiting heart transplant resulted in a reduction of the peripheral eosinophilia, and the eosinophilic myocarditis in the explanted heart [43].

No data are available about the presence of DR on basophils, as well as about a possible role of DA as modulator of basophils’ functions.

Mast cells were first described in 1878 by Paul Erlich. These cells have very a long lifespan and represent a multifunctional immune cell subtype characterized by the presence of large granules. They are found in most tissues of the body, with a particular high density in the airways. The primary role of these cells is to react to allergens. Mast cells circulate in the bloodstream in an immature form before the differentiation in the tissues. After the recognition of a pathogen, the activation of these cells causes the release of several granules containing histamine, tumor necrosis factor (TNF)-α and IL-4 through which they can modulate the immune response.

Mast cells, mainly present in the airways, contain DA and express the rate-limiting enzyme tyrosine hydroxylase (TH), necessary for the biosynthesis of DA [44]. Several dopaminergic agents showed a dose-dependent inhibition of mast cell degranulation, but this effect seemed not to be related with DR [45]. This, however, is in contrast to the data of Mori and colleagues, showing that treatment with DA induces mast cell degranulation, and that the use of a D1-like antagonist prevented this effect [46].

Monocytes and macrophages, together with dendritic cells, constitute the mononuclear phagocyte system which plays a key role maintaining tissue integrity during development and its restoration after injury. Monocytes after developing from myeloid precursors in the bone marrow enter the blood circulation, where they circulate for a few days and then migrate into tissues to complete their maturation into tissue macrophages. Under specific stimuli coming from different chemokines and cytokines, they are rapidly recruited into damaged tissues. Other functions ascribed to these cells are the control of development, homeostasis, and tissue repair [47]. Due to their heterogeneity, monocytes are divided into subsets based on the different stages of differentiation, size and activation.

Macrophages are able to embody microorganisms and damaged tissues. They originate from monocytes, which leave the bloodstream, as mentioned above, and undergo morpho-functional changes in response to several differentiation factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) [48].

Several studies indicate that human monocytes and macrophages express DRs both at mRNA and protein levels, express all five subtypes of dopamine receptors, and are able to produce DA [35,49]. In monocyte-derived macrophages treated with LPS, DA decreases TNF-α production, but up-regulates IL-6 and IL-10 production [49]. Also, DA can decrease LPS-induced proliferation of human monocytes and, acting on DR D1, prevent systemic and neuro-inflammation in vivo [50].

In mouse macrophages, DA suppresses the production of IL-12, a major Th1-related and pro-inflammatory cytokine, but potentiates the secretion of IL-10, a key anti-inflammatory and immunosuppressive cytokine [51]. The above-mentioned effects may explain, to some extent, the evidence that in macrophages inoculated with HIV virus, the treatment with DA leads to an increase of virus replication. Similarly, macrophages of cerebral areas rich of DA are more susceptible to virus infection, and these effects seems to involve D2-like receptors [52].

Microglia were originally described in 1932 by Pío del Rio-Hortega, these cells show a unique phenotype different from both glia and neurons [53]. Microglia are divided into subpopulations according to anatomical location: perivascular microglia, mainly within the basal lamina of a blood vessel and juxtavascular microglia, externally in contact with the basal lamina of the blood vessel [54].

An unregulated activation of microglia in response to environmental stimuli may propagate neuronal injury and be responsible for the neurodegeneration that occurs in several pathologies like Alzheimer’s and Parkinson’s diseases, as well as multiple sclerosis [55]. The five DR are expressed in cultured murine and rat glial cells [56]. Yet human microglia all express DR with the exception of DR D1[57]. The data about the dopaminergic regulation of microglia has been recently revised in detail by Gaskill and colleagues [58].

Dendritic cells (DC) are antigen-presenting cells, which possess high phagocytic activity as immature cells, and high cytokine producing ability, as mature cells. Their pivotal function is to present the antigens to the T cells. DCs express DRs and are able to produce and store DA [59, 60].

In human monocyte-derived dendritic cells, DA dose dependently increases cAMP levels via D1-like receptors and shifts the T-cell differentiation towards the Th2 phenotype. Thus, DA functions as a Th2-polarizing factor at the DC-naive T-cell interface [60]. In addition, the production of IL-12, an important marker of DC maturation, is also modified by the treatment with haloperidol, a D2-like DR antagonist, which attenuate its production and consequently reduce cells maturation [61].

Natural Killer (NK) cells are a subpopulation of lymphocyte-related cells that recognize and kill infected and/or damaged cells by secreting inflammatory cytokines such as GM-CSF, TNF-α, interferon (IFN)-γ, and chemokines such as macrophage inflammatory protein (MIP)-1, CC chemokine ligand (CCL)3, CCL4 and CCL5 [62].

NK express on their surface DRs [35]. The use of D1-like DR agonist enhanced NK cytotoxicity, while the D2-like DR agonist showed opposite effects [63]. In human peripheral-blood derived NK, drugs acting as dopaminergic antagonists may inhibit NK cell responses. Thus, the different activation of the dopaminergic system can influence the killing capacity of NK. In fact, spleen-derived NK of rats with a hyperactive dopaminergic system had a reduced killing capacity compared to those of hypo-dopaminergic rats [64].

Astrocytes are the most abundant non-excitable cells of the brain. They are divided into two principal subtypes: protoplasmic, mostly found in the grey matter, and fibrous, in the white matter [65]. The most important functions of these cells include the regulation of blood flow, their close interaction with blood vessels and their role played in the formation and elimination of synapses. They have a role not only in physiological, but also in pathological conditions such as Rett syndrome, fragile X mental retardation, Alexander’s disease and maybe in Down syndrome [66].

Astrocytes can be influenced by DA by inducing the intracellular calcium signaling [67] and stimulating cAMP production in cultured rat striatal astrocytes [68].

Dopamine and immune-mediated diseases

Different studies demonstrate the role of peripheral immunity in neurodegenerative and immune-mediated diseases, like multiple sclerosis (MS) [69] rheumatoid arthritis (RA) [31] and HIV [58].

Multiple sclerosis is a demyelinating neurodegenerative disease with lesions in the central nervous system. In this pathology, damage and loss of myelin occurs in multiple areas. The process of demyelination determines the formation of plaques that can evolve from an initial inflammatory phase to a chronic phase, in which they assume characteristics similar to scars. The substantial involvement of dopaminergic pathways in MS is clearly demonstrated in different studies [70] that highlight the key role of DRs D5, which increase their expression in the course of the disease [29]. However, most of the evidence relates to acquired immunity, little is known about the involvement of innate immunity. It is known that in MS monocytes and DC exert a key role in antigen presentation, leading to promotion of inflammation and tissue damage, contributing to the breakdown of the blood-brain barrier and facilitating the trafficking of T cells within the CNS [71, 72]. Mast cells, as well as neutrophils, also participate in the progression of disease, for example, exacerbating the inflammatory status in the early development of EAE in rodent model [73].

Rheumatoid arthritis (RA) is a chronic, systemic and disabling inflammatory disease with most likely autoimmune origin. In RA, innate immunity plays a pivotal role. Macrophages infiltrating the synovial fluid show an inflammatory phenotype releasing pro-inflammatory cytokines such as IL-1β [74]. Neutrophils, DCs and NK cells also participate in the development of the pathology, releasing inflammatory mediators [75-77]. Regarding the involvement of the dopaminergic system in RA, it has been shown that DRs increase their expression in synovial fibroblasts [78]. Moreover, in rats, treatment with haloperidol, a D2-like DR antagonist, reduced immunological, pro-inflammatory and oxidative stress biomarkers, in the complete Freund’s adjuvant-induced arthritis model [79]. To date, no studies are available evaluating the relationship between dopaminergic pathways and innate immune cells in the specific context of RA.

Amyotrophic lateral sclerosis (ALS) is a degenerative disease that affects the brain cells responsible for controlling the muscles, progressively compromising the movements of the voluntary musculature. Several lines of evidence suggest a potential involvement of innate immunity in the pathogenesis of ALS. In the mouse model, Zondler and colleagues emphasize the importance of peripheral monocytes in the ALS pathogenesis and point out on the protective role of monocytes in the early phase of the disease [80].

In 1998, the group of Borasio [81] demonstrated a deficit in the nigrostriatal pathway using single-photon emission computed tomography. Also, in vivo studies evidenced a decreased DRs D2 binding in the striatum of ALS patients [82]. The involvement of DRs D2 in this pathology was confirmed by a recent study, where the use of bromocriptine, a DRs D2 agonist, slows the progression of ALS [83]. Nevertheless, the involvement and/or the dysregulation of immune cells DR pathways in ALS remains poorly understood.

Alzheimer’s disease (AD), a progressive neurodegenerative disease, represents the most common form of dementia with a progressive loss of cognitive functions. The role of the dopaminergic system in AD is still debated, even if the degeneration of dopaminergic neurons is linked with a deterioration of cognitive tasks [84]. Alzheimer’s disease  also displays alterations of striatal D2 receptors that may be part of the pathologic abnormalities and may participate in the extrapyramidal manifestations that occur in this condition [85].

Several studies indicate the possible involvement of innate immunity in AD. Neutrophils were observed by in vivo imaging techniques in the amyloid plaques where they infiltrated and contributed to the inflammatory status by secretion of pro-inflammatory cytokines [86]. Neutrophil depletion reduces the severity of AD progression [87]. In addition, the monocytes in AD patients possess the pro-inflammatory phenotype [88].

HIV is a virus that attacks the cells of immune system, primarily CD4+ T cells and macrophages. Based on current knowledge, HIV is divided into two strains: HIV-1 and HIV-2. HIV-1 is the most virulent, most infectious and the cause of most HIV infections worldwide. It is mainly located in Europe, America and Central Africa. HIV-2, on the other hand, is found mostly in West Africa and Asia and causes a clinically more moderate syndrome compared to the previous strain.

The primary targets of HIV are macrophages, as suggested by the presence of the virus in the conventional sites of macrophages, like meninges and the perivascular areas [89]. DA has a very strong impact on the function of macrophages and was observed that the elevated level of DA in drug abusers correlated with an increased entry of the virus in macrophages [90]. This massive entry is linked to the activation of DR on macrophages. In fact, the use of a pan antagonist for DR eliminates this effect [90]. In addition, DC and NK cells play an antiviral effect [91].

Septic shock is a systemic syndrome due to a serious infection with sepsis. It involves the entire organism, even if the infectious agent is only presented at a particular body site. DA, together with others inotropes, is the first vasopressor used that increased blood pressure and flow and vasodilatation [92]. During sepsis, DA exerts an immune-suppressive effect against neutrophils and macrophages, inhibiting cytokine secretion [93].

In conclusion, we highlighted recent evidence that DA influences key functions of innate immune cells, acting differently depending on the interaction with D1- or D2-like receptors. This includes the production of cytokines, chemotaxis and the expression of surface markers, and the polarization towards Th2 cells responses.

Of note, it is known that in pathologies such as multiple sclerosis the expression of DRs on the cells of acquired immunity correlate with disease activity and development, and is modified by the correspondent treatment. It could therefore be useful to analyze, upstream, the influence exerted by DA on the cells of innate immunity, as they are able to modify the activity of acquired immunity.

This approach may justify further studies and suggests new therapeutic strategies in counteracting the cell activation and tissues invasion, known to be the first step in the majority of immune-mediated diseases, including inflammatory diseases of the CNS.

Author Affiliations

Monica Pinoli – Center of Research in Medical Pharmacology, University of Insubria, Via Ottorino Rossi n. 9, 21100 Varese, VA, Italy.

Acknowledgments

The contents of this article were adapted from Pinoli M, Marino F, Cosentino M. Dopaminergic Regulation of Innate Immunity: a Review. J Neuroimmune Pharmacol. (2017). doi: 10.1007/s11481-017-9749-2.

References:

  1. Basu S, Dasgupta PS (2000). Dopamine, a neurotransmitter, influences the immune system. J Neuroimmunol 102(2):113-24.
  2. Sarkar C, Basu B, Chakroborty D, Dasgupta PS, Basu S (2010). The immunoregulatory role of dopamine: an update. Brain Behav Immun 24(4):525-8. doi: 10.1016/j.bbi.2009.10.015.
  3. Levite M (2012). Nerve-Driven Immunity Neurotransmitters and Neuropeptides in the Immune System. In: Nerve-Driven Immunology (ed) Vienna, Austria and New York, USA: Springer, pp 1-45
  4. Carlsson A, Falck B, Hillarp NA (1962). Cellular localization of brain monoamines. Acta Physiol Scand Suppl. 56:1–28.
  5. Feldman RS, Meyer JS, Quenzer LF (1997). Catecholamines in: Principles of neuropsychopharmacology, Sunderland, Massachusets, USA: Sinauer Associates Inc., pp 277–344.
  6. Anden NE, Carlsson A, Dahlstroem A, Fuxe K, Hillarp NA, Larsson K (1964). Demonstration and mapping out of nigro-neostriatal dopamine neurons. Life Sci 3:523-30
  7. Dahlstroem A, Fuxe K (1964). Localization of monoamines in the lower brain stem. Experientia 20(7):398-9
  8. Cenci MA (2007). Dopamine dysregulation of movement control in L-DOPA induced dyskinesia. Trends Neurosci 30(5):236-43.
  9. Dayan P (2009). Dopamine, reinforcement learning, and addiction. Pharmacopsychiaty 42(1): S56-65. doi: 10.1055/s-0028-1124107
  10. Wise RA (2008). Dopamine and reward: the anhedonia hypotesis 30 years on. Neurotox Res 14(2-3):169-83. doi: 10.1007/BF03033808
  11. Sarkar C, Chakroborty D, Basu S (2013). Neurotransmitters as regulators of tumor angiogenesis and immunity: the role of catecholamines. J Neuroimmune Pharmacol 8(1):7-14. doi: 10.1007/s11481-012-9395-7.
  12. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998). Dopamine receptors: from structure to function. Physiol Rev 78(1):189-225.
  13. Zhang MZ, Yao B, Wang S, Fan X, Wu G, Yang H, Yin H, Yang S, Harris RC (2011). Intrarenal dopamine deficiency leads to hypertension and decreased longevity in mice. J Clin Invest. 121(7):2845-54. doi: 10.1172/JCI57324.
  14. Eisenhofer G, Aneman A, Friberg P, Hooper D, Fåndriks L, Lonroth H, Hunyady B, Mezey E (1997) Substantial production of dopamine in the human gastrointestinal tract. J Clin Endocrinol Metab 82:3864-3871. doi:10.1210/jcem.82.11.4339.
  15. Eichler I, Eichler HG, Rotter M, Kyrle PA, Gasic S, Korn A (1989) Plasma concentrations of free and sulfoconjugated dopamine, epinephrine, and norepinephrine in healthy infants and children. Klin Wochenschr 67:672–675.
  16. Kulma A, Szopa J (2007). Catecholamines are active compounds in plants. Plant Sci 172(3):433-440.
  17. Murata K, Noda K, Kohno K, Samejima M (1988) Bioavailability and pharmacokinetics of oral dopamine in dogs. J Pharm Sci 77:565–568.
  18. Sibley DR, Monsma FJ Jr, Shen Y (1993). Molecular neurobiology of dopaminergic receptors. Int Rev Neurobiol. 35:391-415.
  19. Beaulieu JM, Gainetdinov RR (2011). The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 63(1):182-217. doi: 10.1124/pr.110.002642.
  20. Beaulieu JM, Espinoza S, Gainetdinov RR (2015). Dopamine receptors – IUPHAR Review 13. Br J Pharmacol. 172(1):1-23.
  21. Kahn ZU, Mrzljak L, Gutierrez A, de la Calle A, Goldman-Rakic PS (1998). Prominence of the dopamine D2 short isoform in dopaminergic pathways. Proc Natl Acad Sci U S A. 95(13):7731-6.
  22. Perreault ML, Hasbi A, O’Dowd BF, George SR (2014). Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance. Neuropsychopharmacology. 39(1):156-68. doi: 10.1038/npp.2013.148.
  23. Casadó-Anguera V, Bonaventura J, Moreno E, Navarro G, Cortés A, Ferré S, Casadó V (2016). Evidence for the heterotetrameric structure of the adenosine A2A-dopamine D2 receptor complex. Biochem Soc Trans. 44(2):595-600. doi: 10.1042/BST20150276.
  24. Ferrè S, Bonaventura J, Tomasi D, Navarro G, Moreno E, Cortés A, Lluís C, Casadó V, Volkow ND (2016). Allosteric mechanisms within the adenosine A2A-dopamine D2 receptor heterotetramer. Neuropharmacology. 104:154-60. doi: 10.1016/j.neuropharm.2015.05.028.
  25. Ferrè S, Lluı´s C, Lanciego JL, Franco R (2010). Prime time for G-protein-coupledvreceptor heteromers as therapeutic targets for CNS disorders: the dopamine D(1)-D(3) receptor heteromer. CNS Neurol Disord Drug Targets 9: 596–600.
  26. Maggio R, Millan MJ (2010). Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance. Curr Opin Pharmacol 10: 100–107.
  27. So CH, Verma V, Alijaniaram M, Cheng R, Rashid AJ, O’Dowd BF et al. (2009). Calcium signaling by dopamine D5 receptor and D5-D2 receptor hetero-oligomers occurs by a mechanism distinct from that for dopamine D1-D2 receptor hetero-oligomers. Mol Pharmacol 75: 843–854.
  28. Bergquist J, Silberring J (1998). Identification of catecholamines in the immune system by electrospray ionization mass spectrometry. Rapid Commun Mass Spectrom. 12(11):683-8.
  29. Zaffaroni M, Marino F, Bombelli R, Rasini E, Monti M, Ferrari M, Ghezzi A, Comi G, Lecchini S, Cosentino M (2008). Therapy with interferon-beta modulates endogenous catecholamines in lymphocytes of patients with multiple sclerosis. Exp Neurol. 214(2):315-21. doi: 10.1016/j.expneurol.2008.08.015.
  30. Cosentino M, Marino F (2013) Adrenergic and dopaminergic modulation of immunity in multiple sclerosis: teaching old drugs new tricks? J NeuroImmune Pharmacol 8:163–179. doi:10.1007/s11481-012-9410-z.
  31. Capellino S, Cosentino M, Wolff C, Schmidt M, Grifka J, Straub RH (2010). Catecholamine-producing cells in the synovial tissue during arthritis: modulation of sympathetic neurotransmitters as new therapeutic target. Ann Rheum Dis. 69(10):1853-60. doi: 10.1136/ard.2009.119701.
  32. González H, Contreras F, Prado C, Elgueta D, Franz D, Bernales S, Pacheco R (2013) Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons during Parkinson’s disease. J Immunol 190:5048–5056. doi:10.4049/jimmunol.1203121.
  1. Pinoli M, Schembri L, Scanzano A, Legnaro M, Rasini E, Luini A, de Eguileor M, Pulze L, Marino F, Cosentino M (2016). Production of proinflammatory mediators by human neutrophils during long-term culture. Int J Clin Exp Pathol 9(2):1858-1866.
  2. Kolaczkowska E, Kubes P (2013). Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 13(3):159-75. doi: 10.1038/nri3399.
  3. McKenna F, McLaughlin PJ, Lewis BJ, Sibbring GC, Cummerson JA, Bowen-Jones D, Moots RJ (2002). Dopamine receptor expression on human T- and B-lymphocytes, monocytes, neutrophils, eosinophils and NK cells: a flow cytometric study. J Neuroimmunol 132(1-2):34-40.
  4. Yamazaki M, Matsuoka T, Yasui K, Komiyama A, Akabane T (1989). Dopamine inhibition of superoxide anion production by polymorphonuclear leukocytes. J Allergy Clin Immunol 83(5):967-72.
  5. Wenisch C, Parschalk B, Weiss A, Zedwitz-Liebenstein K, Hahsler B, Wenisch H, Georgopoulos A, Graninger W (1996). High-dose catecholamine treatment decreases polymorphonuclear leukocyte phagocytic capacity and reactive oxygen production. Clin Diagn Lab Immunol 3(4):423-8.
  6. Sookhai S, Wang JH, Winter D, Power C, Kirwan W, Redmond HP (2000). Dopamine attenuates the chemoattractant effect of interleukin-8: a novel role in the systemic inflammatory response syndrome. Shock 14(3):295-9.
  7. Trabold B, Gruber M, Fröhlich D (2007). Functional and phenotypic changes in polymorphonuclear neutrophils induced by catecholamines. Scand Cardiovasc J 2007, 41(1):59-64
  8. Cordano C, Pardini M, Cellerino M, Schenone A, Marino F, Cosentino M (2015). Levodopa-induced neutropenia. Parkinsonism Relat Disord. 21(4):423-5. doi: 10.1016/j.parkreldis.2015.02.002.
  9. Sookhai S, Wang JH, McCourt M, O’Connell D, Redmond HP (1999). Dopamine induces neutrophil apoptosis through a dopamine D-1 receptor-independent mechanism. Surgery 126(2):314-22.
  10. Rothenberg ME, Hogan SP (2006). The eosinophil. Annu Rev Immunol 24:147-74.
  11. Takkenberg JJ, Czer LS, Fishbein MC, Luthringer DJ, Quartel AW, Mirocha J, Queral CA, Blanche C, Trento A (2004). Eosinophilic myocarditis in patients awaiting heart transplantation. Crit Care Med 32(3):714-21.
  12. Rönnberg E, Calounova G, Pejler G (2012). Mast cells express tyrosine hydroxylase and store dopamine in a serglycin-dependent manner. Biol Chem 393(1-2):107-12.
  13. Seol IW, Kuo NY, Kim KM (2004). Effects of Dopaminergic Drugs on the Mast Cell Degranulation and Nitric Oxide Generation in RAW 264.7 Cells. Arch Pharm Res 27(1): 94-98.
  14. Mori T, Kabashima K, Fukamachi S, Kuroda E, Sakabe J, Kobayashi M, Nakajima S, Nakano K, Tanaka Y, Matsushita S, Nakamura M, Tokura Y (2013). D1-like dopamine receptors antagonist inhibits cutaneous immune reactions mediated by Th2 and mast cells. J Dermatol Sci 71(1):37-44. doi: 10.1016/j.jdermsci.2013.03.008.
  15. De Kleer I, Willems F, Lambrecht B, Goriely S (2014). Ontogeny of myeloid cells. Front Immunol 5:423. doi: 10.3389/fimmu.2014.00423.
  16. Parihar A, Eubank TD, Doseff AI (2010). Monocytes and macrophages regulate immunity through dynamic networks of survival and cell death. J Innate Immun 2(3):204-15. doi: 10.1159/000296507.
  17. Gaskill PJ, Carvallo L, Eugenin EA, Berman JW (2012). Characterization and function of the human macrophage dopaminergic system: implications for CNS disease and drug abuse. J Neuroinflammation 2012, 18;9:203. doi: 10.1186/1742-2094-9-203.
  18. Yan Y, Jiang W, Liu L, Wang X, Ding C, Tian Z, Zhou R (2015) Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell 160:62–73. doi:10.1016/j.cell.2014.11.047.
  19. Haskó G, Szabó C, Németh ZH, Deitch EA (2002). Dopamine suppresses IL-12 p40 production by lipopolysaccharide-stimulated macrophages via a beta-adrenoceptor-mediated mechanism. J Neuroimmunol 122(1-2):34-9.
  20. Gaskill PJ, Calderon TM, Luers AJ, Eugenin EA, Javitch JA, Berman JW (2009). Human immunodeficiency virus (HIV) infection of human macrophages is increased by dopamine: a bridge between HIV-associated neurologic disorders and drug abuse. Am J Pathol 175(3):1148-59. doi: 10.2353/ajpath.2009.081067.
  21. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011). Physiology of microglia. Physiol Rev. 91(2):461-553. doi: 10.1152/physrev.00011.2010.
  22. Gehrmann J, Matsumoto Y, Kreutzberg GW (1995). Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev. 20(3):269-87.
  23. Block ML, Hong JS (2005). Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism. Prog Neurobiol. 76(2):77-98.
  24. Huck JH, Freyer D, Böttcher C, Mladinov M, Muselmann-Genschow C, Thielke M, Gladow N, Bloomquist D, Mergenthaler P, Priller J (2015). De novo expression of dopamine D2 receptors on microglia after stroke. J Cereb Blood Flow Metab. 35(11):1804-11. doi: 10.1038/jcbfm.2015.128.
  25. Mastroeni D, Grover A, Leonard B, Joyce JN, Coleman PD, Kozik B, Bellinger DL, Rogers J (2009). Microglial responses to dopamine in a cell culture model of Parkinson’s disease. Neurobiol Aging. 30(11):1805-17. doi: 10.1016/j.neurobiolaging.2008.01.001.
  26. Gaskill PJ, Calderon TM, Coley JS, Berman JW (2013). Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND. J Neuroimmune Pharmacol. 8(3):621-42. doi: 10.1007/s11481-013-9443-y.
  27. Nakano K, Higashi T, Hashimoto K, Takagi R, Tanaka Y, Matsushita S (2008). Antagonizing dopamine D1-like receptor inhibits Th17 cell differentiation: Preventive and therapeutic effects on experimental autoimmune encephalomyelitis. Biochem biophys Res Commun 373: 286-291. doi: 10.1016/j.bbrc.2008.06.012.
  28. Nakano K, Higashi T, Takagi R, Hashimoto K, Tanaka Y, Matsushita S (2009). Dopamine released by dendritic cells polarizes Th2 differentiation. Int Immunol 21(6):645-654. doi: 10.1093/intimm/dxp033.
  29. Matsumoto A, Ohta N, Goto Y, Kashiwa Y, Yamamoto S, Fujino Y (2015). Haloperidol Suppresses Murine Dendritic Cell Maturation and Priming of the T Helper 1–Type Immune Response. Anesth Analg 120(4):895-902. doi: 10.1213/ANE.0000000000000606.
  30. Walzer T, Dalod M, Robbins SH, Zitvogel L, Vivier E (2005). Natural-killer cells and dendritic cells : “l’union fait la force”. Blood 106(7):2252-8.
  31. Zhao W, Huang Y, Liu Z, Cao BB, Peng YP, Qiu YH (2013). Dopamine Receptors Modulate Cytotoxicity of Natural Killer Cells via cAMP-PKA-CREB Signaling Pathway. PLoS One 2013, 8(6):e65860. doi: 10.1371/journal.pone.0065860.
  32. Teunis MA, Heijnen CJ, Cools AR, Kavelaars A (2004). Reduced splenic natural killer cell activity in rats with a hyperreactive dopaminergic system. Psychoneuroendocrinology 2004, 29(8):1058-64
  33. Sofroniew M, Vinters HV (2010). Astrocytes: biology and pathology. Acta Neuropathol. 119(1):7-35. doi: 10.1007/s00401-009-0619-8.
  34. Molofsky AV, Krencik R, Ullian EM, Tsai HH, Deneen B, Richardson WD, Barres BA, Rowitch DH (2012). Astrocytes and disease: a neurodevelopmental perspective. Genes Dev. 26(9):891-907. doi: 10.1101/gad.188326.112.
  35. Vaarmann A, Ghandi S, Abramov AY (2010). Dopamine Induces Ca2+ Signaling in Astrocytes through Reactive Oxygen Species Generated by Monoamine Oxidase. J Biol Chem. 2010 285(32):25018-23. doi: 10.1074/jbc.M110.111450.
  36. Zanassi P, Paolillo M, Montecucco A, Avvedimento EV, Schinelli S (1999). Pharmacological and molecular evidence for dopamine D(1) receptor expression by striatal astrocytes in culture. J Neurosci Res. 58(4):544-52.
  37. Marino F, Cosentino M (2016). Multiple sclerosis: Repurposing dopaminergic drugs for MS–the evidence mounts. Nat Rev Neurol. 12(4):191-2. doi: 10.1038/nrneurol.2016.33.
  38. Pacheco R, Contreras F, Zouali M (2014). The dopaminergic system in autoimmune diseases. Front Immunol. 5:117. doi: 10.3389/fimmu.2014.00117.
  39. Prado C, Contreras F, Gonzalez H, Diaz P, Elgueta D, Barrientos M, Herrada AA, Lladser A, Bernales S, Pacheco R (2012). Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-mediated immunity. The Journal of Immunology 188:3062-3070. doi: 10.4049/jimmunol.1103096.
  40. Waschbisch A, Manzel A, Linker RA, Lee DH (2011) Vascular pathology in multiple sclerosis: mind boosting or myth busting? Exp Transl Stroke Med. doi:10.1186/2040-7378-3-7.
  41. Hertwig L, Pache F, Romero-Suarez S, Stürner KH, Borisow N, Behrens J, Bellmann-Strobl J, Seeger B, Asselborn N, Ruprecht K, Millward JM, Infante-Duarte C, Paul F (2016). Distinct functionality of neutrophils in multiple sclerosis and neuromyelitis optica. Mult Scler. 2016 Feb;22(2):160-73. doi: 10.1177/1352458515586084.
  42. Gierut A, Perlman H, Pope RM (2010). Innate Immunity and Rheumatoid Arthritis. Rheum Dis Clin North Am. 36(2):271-96. doi: 10.1016/j.rdc.2010.03.004.
  43. Wright HL, Moots RJ, Edwards SW (2014). The multifactorial role of neutrophils in rheumatoid arthritis. Nat Rev Rheumatol. 10(10):593-601. doi: 10.1038/nrrheum.2014.80.
  44. Lutzky V, Hannawi S, Thomas R (2007). Cells of the synovium in rheumatoid arthritis. Dendritic cells. Arthritis Res Ther. 9(4):219.
  45. Falgarone G, Jaen O, Boissier MC (2005). Role for Innate Immunity in Rheumatoid Arthritis. Joint Bone Spine. 72(1):17-25.
  46. Capellino S, Cosentino M, Luini A, Bombelli R, Lowin T, Cutolo M, Marino F, Straub RH (2014). Increased Expression of Dopamine Receptors in Synovial Fibroblasts From Patients With Rheumatoid Arthritis. Arthritis Rheumatol. 66(10):2685-93. doi: 10.1002/art.38746.
  47. Fahmy Wahba MG, Shehata Messiha BA, Abo-Saif AA (2015). Ramipril and haloperidol as promising approaches in managing rheumatoid arthritis in rats. Eur J Pharmacol. 765:307-15. doi: 10.1016/j.ejphar.2015.08.026.
  48. Zondler L, Müller K, Khalaji S, Bliederhäuser C, Ruf WP, Grozdanov V, Thiemann M, Fundel-Clemes K, Freischmidt A, Holzmann K, Strobel B, Weydt P, Witting A, Thal DR, Helferich AM, Hengerer B, Gottschalk KE, Hill O, Kluge M, Ludolph AC, Danzer KM, Weishaupt JH (2016) Peripheral monocytes are functionally altered and invade the CNS in ALS patients. Acta Neuropathol 132:391-411. doi:10.1007/s00401-016-1548-y.
  49. Borasio GD, Linke R, Schwarz J, Schlamp V, Abel A, Mozley PD, Tatsch K (1998) Dopaminergic deficit in amyotrophic lateral sclerosis assessed with [I-123] IPT single photon emission computed tomography. J Neurol Neurosurg Psychiatry 65:263–265.
  50. Vogel DY, Vereyken EJ, Glim JE, Heijnen PD, Moeton M, van der Valk P, Amor S, Teunissen CE, van Horssen J, Dijkstra CD (2013). Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status. J Neuroinflammation. 10:35. doi: 10.1186/1742-2094-10-35.
  51. Nagata E, Ogino M, Iwamoto K, Kitagawa Y, Iwasaki Y, Yoshii F, Ikeda JE; ALS Consortium Investigators (2016) PLoS One 24;11: e0149509. doi: 10.1371/journal.pone.0149509.
  52. Nobili A, Latagliata EC, Viscomi MT, Cavallucci V, Cutuli D, Giacovazzo G, Krashia P, Rizzo FR, Marino R, Federici M, De Bartolo P, Aversa D, Dell’Acqua MC, Cordella A, Sancandi M, Keller F, Petrosini L, Puglisi-Allegra S, Mercuri NB, Coccurello R, Berretta N, D’Amelio M (2017) Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease. Nat Commun 8:14727. doi:10.1038/ncomms14727.
  53. Pizzolato G, Chierichetti F, Fabbri M, Cagnin A, Dam M, Ferlin G, Battistin L (1996) Reduced striatal dopamine receptors in Alzheimer’s disease: single photon emission tomography study with the D2 tracer [123I]-IBZM. Neurology 47:1065–1068.
  54. Baik SH, Cha MY, Hyun YM, Cho H, Hamza B, Kim DK, Han SH, Choi H, Kim KH, Moon M, Lee J, Kim M, Irimia D, Mook-Jung I (2014)Migration of neutrophils targeting amyloid plaques in Alzheimer’s disease mouse model. Neurobiol Aging 35:1286–1292. doi:10.1016/j.neurobiolaging.2014.01.003.
  55. Zenaro E, Pietronigro E, Della Bianca V, Piacentino G, Marongiu L, Budui S, Turano E, Rossi B, Angiari S, Dusi S, Montresor A, Carlucci T, Nanì S, Tosadori G, Calciano L, Catalucci D, Berton G, Bonetti B, Constantin G (2015) Neutrophils promote Alzheimer’s disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med 21:880–886. doi:10.1038/nm.3913.
  56. Saresella M, Marventano I, Calabrese E, Piancone F, Rainone V, Gatti A, Alberoni M, Nemni R, Clerici M (2014) A complex proinflammatory role for peripheral monocytes in Alzheimer’s disease. J Alzheimers Dis 38:403–413. doi:10.3233/JAD-131160.
  57. Nottet HSLM, Gendelman HE (1995) Unravelling the neuroimmune mechanisms for the HIV-1-associated cognitive/motor complex. Immunol Today 16:441–448.
  58. Gaskill PJ, Yano HH, Kalpana GV, Javitch JA, Berman JW (2014) Dopamine receptor activation increases HIV entry into primary human macrophages. PLoS One. doi:10.1371/journal.pone.0108232
  59. Carrington M, Alter G (2012) Innate immune control of HIV. Cold Spring Harb Perspect Med. doi:10.1101/cshperspect.a007070.
  60. McDonald RH, Goldberg LI, McNay JL, Tuttle NP (1964) Effect of dopamine in man: augmentation of sodium excretion, glomerular filtration rate, and renal plasma flow. J Clin Invest 43:1116–1124. doi:10.1172/JCI104996.
  61. Beck GC, Brinkkoetter P, Hanusch C, Schulte J, van Ackern K, van der Woude FJ, Yard BA (2004) Clinical review: immunomodulatory effects of dopamine in general inflammation. Crit Care 8:485–491. doi:10.1186/cc2879.

 Related stories you may like:

Electroacupuncture, immunity and stimulation of dopaminergic pathway
Endogenous catecholamine in immune cells
Sympathetic nervous system and regulatory T cells

The post The Cross-talk between the Dopaminergic System and Innate Immunity: An Evolving Concept appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
6058
Norepinephrine through β2-adrenoceptor activation down-regulates pro-inflammatory pathogenic Th17 cells in a rodent model of rheumatoid arthritis http://www.brainimmune.com/norepinephrine-though-%ce%b22-adrenoceptor-down-regulates-th17-cells/ Tue, 20 Mar 2018 13:25:56 +0000 http://www.brainimmune.com/?p=6045 What’s Hot A recent study in Medical Science Monitor indicates that norepinephrine (noradrenaline), the major sympathetic nervous system neurotransmitter, through stimulation of β2-adrenoceptors (AR) is able to suppress the highly pathogenic T helper 17 (Th17) cells and exert anti-inflammatory effects in a mouse model of arthritis. In 1986 Mosman et al. discovered the Th1 (mostly […]

The post Norepinephrine through β2-adrenoceptor activation down-regulates pro-inflammatory pathogenic Th17 cells in a rodent model of rheumatoid arthritis appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
What’s Hot

A recent study in Medical Science Monitor indicates that norepinephrine (noradrenaline), the major sympathetic nervous system neurotransmitter, through stimulation of β2-adrenoceptors (AR) is able to suppress the highly pathogenic T helper 17 (Th17) cells and exert anti-inflammatory effects in a mouse model of arthritis.

In 1986 Mosman et al. discovered the Th1 (mostly pro-inflammatory) and Th2 cells (mostly anti-inflammatory) subsets of CD4+ T lymphocytes. About 20 years later, a third Th cell subset called Th17, and producing the cytokine IL-17 (IL-17A) was found. Th17 cells also produce the cytokines IL-17F, IL-22 and GM-CSF and are characterized by the expression of the transcription factor RORγt. Importantly, Th17 cells are the major players in the development and progression of many inflammatory and autoimmune diseases. This includes rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus and multiple sclerosis.

Now is also known that catecholamines (norepinephrine and epinephrine) inhibit the production of Th1/pro-inflammatory, but stimulate the production of Th2/anti-inflammatory cytokines. Thus, sympathetic neuromediators and hormones mediate a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. However, little is known about the effect of catecholamines on Th17 cell functions.

In rheumatoid arthritis, it appears that there is a defect of the systemic anti-inflammatory feedback systems, and locally sympathetic nerve fibers are markedly reduced in the synovial tissue of patients with RA, in contrast to the pro-inflammatory sensory fibers. Likewise, the sympathetic nerve fibers are also reduced in synovial tissue and lymph nodes of animals with collagen-induced arthritis (CIA).

In the Medical Science Monitor study, Yan Liu and colleagues from the Nantong University, Nantong, Jiangsu, China investigated the expression of β2-AR by CD4+ T cells and the effects of norepinephrine on the Th17 cell differentiation and function in the mouse CIA model of rheumatoid arthritis.

The researchers found that CD4+ T cells expressed β2-AR, and the expression was downregulated during the CIA disease progression. It is known that naive CD4+ T cells and effector Th1 (but not Th2) cells express β2-ARs. Here, Liu et al. provide evidence that β2-ARs are also expressed on Th17 cells, and that this expression is reduced by the CIA condition.

While, the CIA disease model induced an increase of IL-17 and IL-22 production, CD25–IL-17+ cell percentage, and the ROR-γt expression in CD4+ T cells, norepinephrine reduced the T cell shift towards Th17 phenotype and a β2-ARs antagonist reversed this effect.

Importantly, the β2-AR agonist terbutaline inhibited the CIA-induced IL-17 and IL-22 expression, and the expression of the Th17 cell-specific transcriptional factor ROR-γt. Terbutaline also reduced the CIA-induced CD4+ T cell proliferation and the shift towards Th17 phenotype though a protein kinase A (PKA)-dependant pathway.

Overall, these results indicate that the sympathetic nervous system neuromediator norepinephrine, though activation of the β2-AR/PKA pathway is able to down-regulate the development and activity of Th17 cells, and thus, in turn to exert anti-inflammatory effects in the mouse CIA arthritis model.

This may also suggest that β2-adrenoceptor agonists hold a theurapeutic potential in rheumatoid arthritis.

Source: Med Sci Monit, 2018, 24:1196-1204.
Read More: Med Sci Monit

The post Norepinephrine through β2-adrenoceptor activation down-regulates pro-inflammatory pathogenic Th17 cells in a rodent model of rheumatoid arthritis appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
6045
An Evolving Concept: The Pathologic Level of Brain TNF is a Therapeutic Target for Chronic Pain Treatment http://www.brainimmune.com/pathologic-level-brain-tnf-therapeutic-target-chronic-pain/ Mon, 12 Mar 2018 12:45:58 +0000 http://www.brainimmune.com/?p=5981 Evolving Concept Chronic pain is a serious healthcare dilemma with many treatment options available, such as antidepressants, non-steroidal anti-inflammatory drugs, opioids, and anticonvulsants; nevertheless, chronic pain presently is not appropriately managed. A fundamental reason for the lack of effective treatment is that none of these drugs specifically target a process that is essential in eliciting […]

The post An Evolving Concept: The Pathologic Level of Brain TNF is a Therapeutic Target for Chronic Pain Treatment appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
Evolving Concept

Chronic pain is a serious healthcare dilemma with many treatment options available, such as antidepressants, non-steroidal anti-inflammatory drugs, opioids, and anticonvulsants; nevertheless, chronic pain presently is not appropriately managed.

A fundamental reason for the lack of effective treatment is that none of these drugs specifically target a process that is essential in eliciting a mechanism fundamental in the etiology of chronic pain pathology. Yet, prescriptions for these drugs, and in particular opioids, are increasingly provided to patients. As a consequence, a recent epidemic of addiction and accidental drug prescription overdoses parallel the increased use of opioids for misguided treatment purposes, because opioids rarely relieve chronic pain fully, may contribute to worsening of pain, and side-effects such as cognitive impairment, nausea, constipation, development of tolerance, and potential for addiction and overdose deaths exist. Accordingly, there is an urgent need for an alternative, non-opiate treatment of chronic pain.

Chronic pain is based on a mental perception with a cognitive feature and occurs subsequent to the development of neuroplastic changes at higher centers of the brain.  With this understanding, we have investigated how a pro-inflammatory cytokine known to be proximally involved in one of the major causes of chronic pain, injury at a peripheral site, and in the development of the inflammatory loci, could at the same time have a fundamental function at higher centers of the brain by simultaneously being involved in neuron functioning.

An extensive understanding of the involvement of a pro-inflammatory cytokine on neuron functioning in the brain may well define and thus elucidate the neuroplastic changes that are integral in the etiology of chronic pain. In fact, the pleiotropic and pro-inflammatory cytokine, tumor necrosis factor-alpha (TNFα), known to orchestrate the cellular reactions in an inflammatory lesion, has been shown to affect not only pathological and inflammatory conditions, but also neurological disorders, and it participates in a seminal role in the maintenance of physiological homeostasis.

Due to these diverse activities, TNFα has been and still is widely investigated. Preclinical studies from our laboratory and others show that heightened levels of TNFα in the brain are both sufficient as well as necessary for the development of chronic pain behaviors, such as hyperalgesia and allodynia [1-5]. It is therefore apparent that by regulating either the expression of or the response to TNFα selectively in the brain, a robust effect would be envisaged on the onset, development and maintenance of chronic pain.

With the goal of testing this hypothesis, we are discovering that drugs that selectively lower TNFα levels and their method of delivery that solely affect levels only in the brain are effective as treatment paradigms in chronic pain animal models. For example, total relief of peripheral hypersensitivity in neuropathic pain models (chronic constriction injury and spared nerve injury) was achieved through the specific blockade of brain TNFα following either direct intracerebroventricular or intracerebral injection [1,3,6].

However, due to the invasiveness of these procedures (requiring drilling of burr holes in the skull and/or inserting needles into the parenchyma of the brain) to achieve brain delivery, the present challenge is to explore novel, peripheral, non-invasive methods for the selective inhibition of TNFα solely in the brain for clinical application. Yet, it is difficult to direct anti-TNFα agents to the brain by peripheral administration, because clinically available TNFα blockers (i.e., etanercept, Infliximab) are large molecules that do not easily enter the brain via standard administration (intravenous, per os) protocols. Only negligible quantities of these biologic agents reach the brain when delivered by standard peripheral routes and therefore have little effect on this organ. Intrathecal injection is often employed in the clinical setting to deliver agents to the cerebrospinal fluid. However, this method of delivery is both invasive, requiring penetration of the ligamentum flavum and the dura using a long spinal needle, and limited with only partial distribution to the ventricles, and with the remainder of the injection having alternate peripheral distribution.

Thus, it is apparent that therapy for the many neurological disorders requires a more direct and non-invasive route for drug delivery/access to the brain. We are currently investigating and establishing the perispinal route of delivery, which completely offers this access [7-9]. The delivery consists of a non-invasive peripheral perispinal injection in the posterior neck region (into the posterior spinal venous plexus), which permits direct drug access to the ventricles of the brain via the choroid plexus following Trendelenburg positioning. The enhanced hydrostatic pressure during Trendelenburg positioning forces a compound through a valve-less system contiguous with the cerebrospinal venous system and into the ventricles. Once in the ventricles, the biologics can intimately communicate with the brain parenchyma.

This therapeutic method is distinct from intrathecal (or epidural) injection, as there is no risk of needle injury to the spinal cord or to the epidural veins since perispinal administration is external to the ligamentum flavum. Targeting TNFα (i.e., decreasing activity) in the brain, as opposed to activating the opioid pathway or other nonspecific mechanism, provides a superior novel pain target that is potent and ready for clinical translation to benefit patients with chronic, treatment-resistant pain.  Based on our experience using this pioneering breakthrough in the clinical setting, we are confident that this technology provides a safe, non-addictive treatment of analgesia, with greater efficacy than current treatments [10,11].

Based on our many years of research along with extensive literature by other investigators, we propose that the directed delivery of drugs that solely dampen TNFα levels in the brain establishes an analgesic mechanism of action necessary for a pioneering breakthrough of novel drugs that are efficacious for treating chronic pain.  Not only would this treat chronic pain, but it would also avoid the myriad side-effects associated with treatment options presently available, effects that prevent their possible true potential. In fact, we also propose that the therapeutic efficacy endowed by compounds such as tricyclic antidepressant drugs is because of their ability to reestablish homeostatic TNFα concentrations within the brain; we have identified the mechanism of decreasing TNFα levels in the brain elicited by tricyclic antidepressant drugs that explains the analgesic property of these drugs and which may be harnessed for effective treatment of chronic pain [12,13]. However, because of their ancillary unwarranted side-effects their use is tentative at best.

In conclusion, our research has shown that by either blocking pathologic TNFα activity or decreasing TNFα production solely in the brain (avoiding peripheral distribution) has profound patient benefits.  This profound effect on chronic pain pathology is mediated through the reduction of the associated role of TNFα as a neuromodulator in addition to its role of orchestrating inflammation. Excess levels of a proximal pro-inflammatory cytokine are usually abnormal, and the administration of specific anti-TNFα compounds can reduce or arrest this inflammatory and aberrant neuromodulatory response effectively. Subsequent to an insult, such as traumatic brain injury, stroke, concussion, or peripheral injury, the disruption of brain-TNFα homeostasis generates maladaptive alterations which produce chronic pain. Achieving reduced inflammation in the brain after succumbing to an insult can restore appropriate brain functions. At such a time, viable tissue remains in a dysfunctional state due to abnormal, unnecessary levels of TNFα. Therefore, it is expected that administration of anti-TNFα biologics via perispinal injection achieves a very efficient decrease in TNFα expression throughout the brain parenchyma.

Authors Affiliation:

Robert N. Spengler, Ph.D.b and Tracey A. Ignatowski, Ph.D.a,baDepartment of Pathology and Anatomical Sciences and Program for Neuroscience, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14203 bNanoAxis, LLC, Clarence, New York 14031

References:

  1. Ignatowski TA, Covey WC, Knight PR, Severin CM, Nickola TJ, Spengler RN. Brain-derived TNFα mediates neuropathic pain. Brain Res, 1999; 841: 70-77.
  2. Covey WC, Ignatowski TA, Knight PR, Spengler RN. Brain-derived TNFα: involvement in neuroplastic changes implicated in the conscious perception of persistent pain. Brain Res, 2000; 859: 113-122.
  3. Gerard E, Spengler RN, Bonoiu AC, Davidson BA, Mahajan SD, Ding H, Kumar R, Prasad PN, Knight PR, Ignatowski TA. Chronic pain is relieved by nanomedicine-mediated decrease of hippocampal TNF. PAIN, 2015; 156: 1320-1333.
  4. Martuscello RT, Spengler RN, Bonoiu AC, Davidson B, Helinski J, Ding H, Mahajan S, Kumar R, Bergey EJ, Knight PR, Prasad PN, Ignatowski TA. Increasing TNF levels solely in the rat hippocampus produces persistent pain-like symptoms. PAIN, 2012; 153: 1871-1882.
  5. Oka, T., Y. Wakugawa, M. Hosoi, K. Oka, and T. Hori. Intracerebroventricular injection of tumor necrosis factor-a induces thermal hyperalgesia in rats.  Neuroimmunomodulation, 1996; 3:135-140.
  6. Li X, Wang J, Wang Z, Dong C, Dong X, Jing Y, Yuan Y, Fan G. Tumor necrosis factor-alpha of Red nucleus involved in the development of neuropathic allodynia. Br Res Bull, 2008; 77(5): 233-236.
  7. Tobinick E. Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother, 2010; 10(6): 985-1002.
  8. Tobinick EL. Perispinal Delivery of CNS Drugs. CNS Drugs, 2016; 30(6): 469-480.
  9. Tobinick E, Ignatowski TA, Spengler RN. On Overcoming Barriers to Application of Neuroinflammation Research, in Mechanisms of Neuroinflammation, 2017; G.E.A. Abreu, Editor.  InTech.
  10. Ignatowski TA, Spengler RN, Dhandapani KM, Folkersma H, Butterworth RF, Tobinick E. Perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and             current evidence. CNS Drugs, 2014; 28(8): 679-697.
  11. Tobinick E, Rodriguez-Romanacce H, Levine A, Ignatowski TA, Spengler RN. Immediate neurological recovery following perispinal etanercept years after brain injury. Clin Drug Investig, 2014; 34(5): 361-366.
  12. Ignatowski TA, Reynolds JL, Sud R, Knight PR, Spengler RN. The dissipation of neuropathic pain paradoxically involves the presence of tumor necrosis factor-α (TNF). Neuropharmacology, 2005; 48: 448-460.
  13. Sud R, Spengler RN, Nader ND, Ignatowski TA. Antinociception occurs with a reversal in α2- adrenoceptor regulation of TNF production by peripheral monocytes/macrophages from pro- to anti-inflammatory. Eur J Pharmacol, 2008; 588: 217-231.

Related stories you may like:

Disruption of brain TNF homeostasis and alterations producing chronic pain
Perispinal etanercept improves neurological function in chronic brain injury
Perispinal delivery of CNS drugs: from Corning to perispinal etanercept
Evidence linking IL-17 to neuropathic pain

The post An Evolving Concept: The Pathologic Level of Brain TNF is a Therapeutic Target for Chronic Pain Treatment appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
5981
2017 in Review: New Advances in Neuroendocrine Immunology http://www.brainimmune.com/2017-review-neuroendocrine-immunology/ Mon, 05 Mar 2018 18:52:04 +0000 http://www.brainimmune.com/?p=5968 Editorial In 2017, we witnessed further rapid growth in the vast interdisciplinary area of neuroendocrine immunology. It became a tradition to reflect on the new significant developments and conceptual trends in the field that were presented at BrainImmune. We will retrace some of our commentaries, revisiting the studies on BrainImmune we believe are illustrative, stimulating […]

The post 2017 in Review: New Advances in Neuroendocrine Immunology appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
Editorial

In 2017, we witnessed further rapid growth in the vast interdisciplinary area of neuroendocrine immunology. It became a tradition to reflect on the new significant developments and conceptual trends in the field that were presented at BrainImmune. We will retrace some of our commentaries, revisiting the studies on BrainImmune we believe are illustrative, stimulating and of general interest. Below is a highly condensed outline of the most interesting research and emerging concepts as covered by BrainImmune.

NEW EVOLVING CONCEPTS
Brain ‘Superautoantigens’ and Autoimmunity

According to Serge Nataf only a limited range of the human ‘self’ antigen library is actually targeted by pathological autoimmunity. Thus, in the context of autoimmunity, “not all ‘self’ antigens are equal with regard to immunogenicity and what could be called ‘superautoantigens’ are more prone to be targeted under pathological conditions”.

Nataf proposes a theoretical model where in humans “a majority of autoantigens that are targeted in common non-CNS autoimmune diseases are indeed brain autoantigens belonging to the synaptic or myelin compartments”.

As per the ‘brain superautoantigens’ theory – the major autoantigens targeted in non-CNS autoimmune disorders belong to the synaptic compartment. One such example is GAD65 (also known as GAD2, glutamate decarboxylase, an enzyme of the GABAergic system) – the main autoantigen in diabetes type 1.

Interestingly, this model also proposes that mechanisms allowing a proper exposure of brain superautoantigens to the immune system have exerted a major leverage evolutionary force. Importantly, the model also admits that the immune and neural repertoires are mutually nourishing throughout the whole life of an individual. This may also suggests that a “pathophysiological re-assessment of conditions usually considered as purely immunological (autoimmune disorders) or purely neurological (autism, schizophrenia, neurodegenerative diseases)” should be considered.

Pro-Inflammatory and Highly Pathogenic Th17 Cells Are Glucocorticoid Resistant

The paradigm of T helper (Th)1 and Th2 cells regulating cellular and humoral immunity dominated until 2000-2005. Shortly after that, however, with the discovery of IL-23 and the third T-cell subset, known as Th17 cells, they received the major attention, primarily because they appear to be the principal players in several autoimmune and inflammatory disorders.

Yet, more recent research indicates that not all Th17 cells are inflammatory.

Elisabetta Profumo outlined the emerging concept that Th17 cells are not a homogenous population but rather consist of different subsets of Th17 cells with distinct phenotype and functions. This reflects their pro- or anti-inflammatory activities and glucocorticoid (GC)-sensitivity.

Thus, the PATHOGENIC PRO-INFLAMMATORY Th17 cells express high levels of IL-23 receptor and integrin avβ3 on their surface, produce the pro-inflammatory cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon (IFN)-γ and express the Th1 transcription factor T-bet, while the PROTECTIVE Th17 cells produce the anti-inflammatory cytokine IL-10.

Recent evidence also indicates that the high PATHOGENIC Th17 cells are GC-RESISTANT. PRO-INFLAMMATORY Th17 cells, producing both IL-17 and (IFN)-γ, express the molecule multi-drug resistance type 1 (MDR1), also known as P-glycoprotein, and these cells are refractory to GC-mediated T cell suppression. Th17 resistance to GCs is also associated with high levels of the anti-apoptotic factor BCL-2, the transcription factor RORγt, STAT3 and high levels of IL-6.

Importantly, the glucocorticoid-resistant pathogenic Th17 cells appear to be the major players driving chronic inflammatory process. Of note, long-term glucocorticoid treatment may deplete GC-sensitive T cells and promote the expansion of GC resistant subsets, thus sustaining the inflammatory process. Interestingly new research suggests that the GC-resistant Th17 are most likely sensitive to the calcineurin inhibitor cyclosporine A.

The ‘Selfish Brain and Immune Systems’ – Energy Deficiency Link

Rainer Straub argues that the selfishness of the brain and immune systems provoke energy deficiency in aging and chronic inflammation. Thus, several chronic inflammation-related signs and symptoms result from a highly active, energy-consuming immune system. But, the same signs and symptoms also are present in elderly individuals, and in chronic inflammatory diseases in remission, without much inflammation.

As the brain requires similar amounts of energy as the immune system, thus, we should also consider here, the energy expenditure of the selfish and active brain.

The new model, suggested by Rainer Straub, takes into consideration “that energy shortage in these groups of individuals depends on increasing energy expenditure caused by high levels of psychomotor activity (brain and muscles). For example, pain, psychological stress, sleeping alterations and anxiety increase energy expenditure”.

Importantly, in the short term, these changes may represent “highly favorable coping mechanisms used by the body in situations of short-lived energy under-supply”. In the long-term, however, the use of these mechanisms may become maladaptive, and in turn, contribute to unfavorable complications.

Thus, as per the author, in chronic inflammatory diseases, physicians and pharmaceutical companies should take an integrative approach and look for solutions beyond immunosuppression.

β2-Adrenoceptor Agonists – Candidates as Novel Non-Conventional Anti-Parkinson’s Drugs

A study published in Science indicated that the β2-adrenoreceptor (β2AR) is a regulator of the α-synuclein gene (SNCA), and may drive the risk of Parkinson’s disease (PD). In 11 years of follow-up in 4 million Norwegians, Shuchi Mittal et al. found that the β2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing PD.

In a recent commentary at BrainImmune Marco Cosentino et al. argued that “the study by Mittal et al. (2017) has the merit to attract novel attention on the possibility to repurpose as antiparkinson drugs the β2-AR agonists, which are well established as bronchodilators in asthma”. Importantly, Cosentino et al. discuss 3 relevant studies where salbutamol improved the therapeutic response to levodopa and the motor performance, and possibly increased muscle mass in PD patients.

The authors of this commentary also address this issue from a different perspective – discussing the role of peripheral adaptive immunity, and the link to neuroinflammation ultimately leading to neurodegeneration.

Thus, T lymphocytes occur in the substantia nigra of parkinsonian brains and T cells from PD patients recognize α-syn peptides. CD4+ T cells may acquire proinflammatory phenotypes, and animal models of PD suggests that Th1 and Th17 cells may be detrimental, whereas Th2 and Treg cells may be protective.

Of note, β2-AR agonists might be beneficial, in this regard, as it is now known that they inhibit Th1 responses but potentiate Th2 cells and cytokines; and perhaps, also enhancing Treg suppressive functions.

Thus, overall, these drugs affect neuroinflammation and neurodegeneration, and favorably affect Th1, Th2 and Treg cells, which are involved in regulation of these processes. Hence, Cosentino et al. suggest that the “β2-AR agonists might be ideal candidates to be tested as novel nonconventional antiparkinson drugs”.

SOME NEW DEVELOPMENTS
Heart electrical conduction – modulated by resident macrophages!

Innate immune cells such as macrophages are present in the heart, but their role in electrical conduction and the heart rhythm is unknown. In 2017, Maarten Hulsmanet et al., provided the first evidence that resident macrophages located at the atrioventricular (AV) node modulate heart electrical conduction and activity of cardiomyocytes.

The AV node, composed by cardiomyocytes conducts electrical impulses between atria and ventricles. This specialized conducting tissue (cardiac, not neural in origin) slows the impulse conduction, thus allowing sufficient time for complete atrial depolarization and contraction (systole) prior to ventricular depolarization and contraction.

Hulsmanet et al. found that in mice, AV macrophages express ion channels and exchangers, and genes associated to electrical conduction. These cells also interact with cardiomyocytes through gap juntion proteins and increase cardiomyocyte resting membrane potentials, suggesting their role in cardiomyocyte repolarization.

As per the authors, myocardial infarction, heart failure, diabetes or inflammatory diseases of the heart such as Chagas, Lyme, sarcoid and myocarditis may contribute to changes in the cardiac macrophages’ phenotype and numbers, which in turn may result in arrhythmias and conduction abnormalities.

Brain IL-6 and Depression

Some inflammatory cytokines profoundly affect brain functions, mood and behavior. Thus, inflammatory mechanisms might be involved in the etiology and pathophysiology of neuropsychiatric disorders such as depression.

A study published in Molecular Psychiatry indicates that the depressive symptoms in inflammatory conditions might be linked to an increase in central IL-6 concentration.

Most read May IL-6Harald Engler and Manfred Schedlowski’s team from the University Hospital Essen, Germany found that in healthy male volunteers the intravenous administration of low-dose endotoxin resulted in a robust and selective increase of IL-6 in the cerebrospinal fluid (CSF).

Of note, the endotoxin-induced increase of IL-6 correlated with the severity of mood impairment, where larger increases in IL-6 CSF concentrations contributed to a greater deterioration in mood.

These results imply IL-6 as an important messenger transferring the inflammatory signal from the body’s periphery to the brain. Thus, the appearance of depressive symptoms in inflammatory conditions might be causally and primarily linked to an increase in brain IL-6 concentrations, identifying IL-6 as a potential therapeutic target in mood disorders.

High IFN-γ and TNF-α versus low IL-10 Levels in Generalized Anxiety Disorder

Generalized anxiety disorder typically includes an excessive, uncontrollable and often irrational worry about events or activities, and is affecting almost 7 million adults or about 3% of the U.S. Population.

BrainImmune covered a study published in Brain, Behavior, and Immunity showing that anxiety is associated with a peripheral imbalance of pro- and anti-inflammatory cytokines.

Ruihua Hou and colleagues, from the University of Southampton, UK found that patients with generalized anxiety had high levels of interferon (IFN)-γ and tumor necrosis factor (TNF)-α, but low IL-10 serum levels when compared to healthy control subjects.

IFN-γ and TNF-α belong to the group of major pro-inflammatory cytokines, whereas IL-10 is a potent anti-inflammatory cytokine. As per the authors of this study, the cytokine ‘signature’ or profile in generalized anxiety patients is specific for this type of pathology.

Major depression is the principal comorbidity of generalized anxiety disorder. Hou R et al. propose that the pro-inflammatory state contribute to the altered activity of an enzyme involved in the metabolism of tryptophan, leading to degradation of serotonin in patients with generalized anxiety, via a mechanism similar to the one seeing in major depression.

Afferent Vagus Stimulation, the Sympathetic Nervous System-Synovial Axis and Joint Inflammation

Vagus nerve stimulation is known to affect immunity and inflammation through a mechanism that involves the peripheral efferent vagus nerve connection to the immune system. Yet, new research suggests that the afferent vagal stimulation also is able to inhibit inflammation, but by unknown brain and spinal cord axis pathway.

2017 in review afferent vagusA study published in the Brain, Behavior, and Immunity provides perhaps the first evidence that stimulation of vagal afferents or specific brain areas modulate joint inflammation, and improves local inflammatory response in experimental arthritis. Bassi and colleagues, from the Medicine College of Ribeirão Preto, Brazil, showed that this new central pathway involves the activation of the sympathetic nervous system, synovial adrenergic innervation and stimulation of local synovial β-adrenoceptors.

The mechanism that reduced experimental joint arthritis, however, was not dependent on the integrity of the spleen, adrenal glands, the celiac vagus or lymphocyte activity. Importantly, the integrity of the brain locus coeruleus (LC), but not that of paraventricular nucleus (PVN), was critical for vagal regulation of the arthritic joint inflammation.

This study show the existence of potential brain immunomodulatory structures (immunological homunculus), and a new central neuroimmune anti-inflammatory pathway dependent on specific sympathomodulatory brain areas, and local sympathetic-synovial-β-adrenergic mechanisms. This pathway may drive anti-inflammatory effects in the body’s periphery.

Hypertension and the Brain-Splenic Nerve Axis

In the past, hypertension was regarded mostly as a dysfunction of the autonomic or sympathetic nervous systems. Recently, however, new evidence suggests that dysfunction at the brain-immune system connection may also contribute to hypertension.

A Nature Communications report indicates the existence of a new sympathetic mechanism in hypertension involving activation of the brain-splenic nerve axis. In other words, and as discussed by the authors of this study, hypertension is a condition where “sympathetic overactivity has effects beyond the kidney and baroreflexes”.

Daniela Carnevale et al. found that the experimental angiotensin II-induced hypertension is driven, to a great extent, by a splenic sympathetic nerve discharge, and that this mechanism is mediated by a vagal-coeliac-splenic connection.

Notably, in the experimental hyperthensive model, splenic denervation prevented the splenic T-cells egress to the systemic circulation and reduced the number of activated T cells to infiltrate into the aorta and kidneys.

On the whole, these experimental data suggests that the cholinergic-sympathetic drive, operating through the vagus-splenic nerve connection, may in turn activate the T cells to migrate to target organs and contribute to blood pressure regulation.

Spinal cord injury – induced immunosuppression linked to an interruption of neuroendocrine reflex involving the sympathetic nervous system and adrenal glands

Spinal cord injury is known to be related to immunosuppression and increased occurrence of infections. Yet, it is unknown whether these changes are due to humoral (via corticosteroids) or neural (via the sympathetic nervous system) disruptions.

A Nature Neuroscience report indicates that life-threatening infections in spinal cord injury patients may be driven by an interruption of the physiological interactions within a neuroendocrine reflex involving the sympathetic nervous system and adrenal glands.

Harald Prüss and colleagues from the Harvard medical school, Boston, Massachusetts found that the experimental thoracic spinal cord transection decreased peripheral norepinephrine (noradrenaline) levels and increased corticosterone levels in mice without activating the hypothalamus–pituitary–adrenal (HPA) axis. The spontaneous pneumonia was associated with decreased norepinephrine and increased corticosterone levels – not dependent on the integrity of the HPA axis – but dependent from a “maladaptive sympathetic-neuroendocrine reflex involving the adrenal glands”.

As per the authors, a two-step reflex mechanism drives these changes, where disruption of the tonic control of the adrenal glands by spinal cord efferents is followed by systemic effects that include low catecholamine levels and increased glucocorticoid release. This may explain the immunosuppressive effects observed after spinal cord injury.

Fibromyalgia and IL-8

Both neuroendocrine dysfunctions, e.g. relentless sympathetic hyperactivity  or immune and cytokine, e.g. IL-8 and IL-17 abnormalities may participate in the pathogenesis of fibromyalgia.

A Journal of Pain Research study documents the presence of high levels of the chemokines interleukin-8 (IL-8) and CX3CL1 (also known as fractalkine) in fibromyalgia patients.

IL-8 FibromyalgiaEmmanuel Bäckryd and colleagues from the Linköping University, Sweden applied the multiplex proximity extension assay, where 92 proteins were simultaneously analyzed in cerebrospinal fluid (CSF) from fibromyalgia patients. The authors found elevated CSF and plasma IL-8 levels, but high levels of CX3CL1 were monitored only in CSF fibromyalgia samples.

Whether this reflects pathophysiology in fibromyalgia, or a risk factor present prior to the development of chronic pain in these patients, remains to be clarified. Interestingly, CX3CL1 is “found throughout the brain, its receptor present on microglial cells”, whereas “IL-8 is the first mediator to be identified as evoking hyperalgesia involving the sympathetic nervous system”.

As “fibromyalgia & related disorders are heterogenous conditions…a continuum with one end a purely peripherally driven painful condition and the other end….where pain is purely centrally driven”, a stratification of FM patients in terms of CX3CL1 and IL-8 levels may, in fact, be existing.

Neuropathic Pain and IL-17

Neuropathic pain or chronic pain is a disease syndrome caused by injury to peripheral nerves, the spinal cord or the brain.

In this condition, the microglial/astrocyte activation or infiltration of macrophages and T cells contribute to central sensitization. Also, pronociceptive factors such as cytokines and chemokines can sensitize neurons of the first pain synapse.

A study in Molecular Medicine Reports indicates that interleukin (IL)-17 drives neuropathic pain via astrocytes activation and secretion of proinflammatory cytokines.

Caixia Sun and colleagues from the Jiangsu University Zhenjiang, China monitored high IL-17 levels in the spinal cord of sciatic nerve-injured rats. This was related to local infiltration of CD4/IL‑17+ cells and increased astrocyte activity.

These cells were associated with an up-regulation of IL‑17, IL‑1β and IL‑6 mRNA expression and high IL-17 protein levels in the spinal cord. Moreover, in vitro, IL‑17 stimulated resting astrocytes to produce IL-1β and IL-6 that may be linked to pain hypersensitivity.

Thus, according to the authors IL‑17 may participate in the pathogenesis of neuropathic pain by promoting astrocytes activation and proliferation, and upregulating proinflammatory cytokines release in the spinal nerve ligation‑induced model of neuropathic pain.

The post 2017 in Review: New Advances in Neuroendocrine Immunology appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
5968
Post Doc Research Fellow Position: Peripheral Immunity in Aging & Parkinson’s http://www.brainimmune.com/post-doc-position-immunity-aging-parkinsons/ Wed, 24 Jan 2018 14:39:30 +0000 http://www.brainimmune.com/?p=5921 PERIPHERAL IMMUNITY in AGING & PARKINSON’S DISEASE: OPEN CALL for 1 Post Doc Research Fellow position (12+12 months) The Center for Research in Medical Pharmacology, University of Insubria (Varese, Italy) works on the role of peripheral immunity in aging and Parkinson’s disease with particular regard to T cells as biomarkers of immunoaging and their relationship […]

The post Post Doc Research Fellow Position: Peripheral Immunity in Aging & Parkinson’s appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
PERIPHERAL IMMUNITY in AGING & PARKINSON’S DISEASE:
OPEN CALL for 1 Post Doc Research Fellow position
(12+12 months)

The Center for Research in Medical Pharmacology, University of Insubria (Varese, Italy) works on the role of peripheral immunity in aging and Parkinson’s disease with particular regard to T cells as biomarkers of immunoaging and their relationship with frailty and PD progression.

The ideal candidate for this Post Doc Research Fellow position (assegno di ricerca) is expected to hold an MD or BSc degree or similar, and to have extensive experience in biomedical research, documented by an appropriate record of publications. In particular, she/he is expected to learn and apply:

  • Flow cytometry techniques for the characterization of main innate and adaptive immune cell subsets in whole blood;
  • Cell separation and culture protocols, with particular regard to human T lymphocyte purification and culture from buffy coats and whole blood;
  • Ex vivo/in vitro functional models of immune response.

Knowledge of scientific English and documented ability to write scientific reports and manuscripts will be a preferential requirement.

The position is open for 1+1 years. Salary will be 25.000,00 €/year (including taxes/social security).

An official call detailing deadlines and procedues will be soon available. Potential applicants are meanwhile invited to submit a pre-application/motivation letter, together with a curriculum vitae including a full list of publications and eventual names for references, at their earliest convenience and possibly not later than February 28th 2018, to farmacologia.medica@uninsubria.it. E-mail submissions must include the subject ‘Post Doc position‘.

References

Cosentino M, Kustrimovic N, Marino F. β2-Adrenergic Agonists for Parkinson’s Disease: Repurposing Drugs at the Crossroad of the Brain and the Immune System. BrainImmune – Trends in Neuroendocrine Immunology (online), 2 december 2017.

Kustrimovic N, Rasini E, Legnaro M, Bombelli R, Aleksic I, Blandini F, Comi C, Mauri M, Minafra B, Riboldazzi G, Sanchez-Guajardo V, Marino F, Cosentino M. Dopaminergic Receptors on CD4+ T Naive and Memory Lymphocytes Correlate with Motor Impairment in Patients with Parkinson’s Disease. Sci Rep. 2016 Sep 22;6:33738.

Marino F, Cosentino M. Multiple sclerosis: Repurposing dopaminergic drugs for MS–the evidence mounts. Nat Rev Neurol. 2016 Apr;12(4):191-2.


See also: uninsubriamedicalpharmacology.blogspot

The post Post Doc Research Fellow Position: Peripheral Immunity in Aging & Parkinson’s appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
5921
Understanding the Role of Inflammation in Fatigue Requires Multidimensional Assessments http://www.brainimmune.com/understanding-role-inflammation-fatigue/ Mon, 22 Jan 2018 14:55:04 +0000 http://www.brainimmune.com/?p=5905 Evolving concepts Introduction “I am tired”. What does this sentence actually imply? In a recent review published in Frontiers in Immunology [1], we suggest that the different dimensions of fatigue (Figure 1) should be specifically investigated, in subjective as well as objective ways. This is especially important if we are to comprehend the role of […]

The post Understanding the Role of Inflammation in Fatigue Requires Multidimensional Assessments appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
Evolving concepts

Introduction

“I am tired”. What does this sentence actually imply? In a recent review published in Frontiers in Immunology [1], we suggest that the different dimensions of fatigue (Figure 1) should be specifically investigated, in subjective as well as objective ways. This is especially important if we are to comprehend the role of inflammation in turning physiological fatigue into pathological fatigue (Figure 2). This notion is further supported by recent publications assessing the role of inflammation in altered motivated behavior, a core dimension of fatigue, in humans [2, 3]. While inflammation is known to induce an overall feeling of loss of motivation, these studies used objective assessment of motivated behavior and indicate that inflammation does not necessarily reduce motivation, but rather reorganizes motivational priorities depending on the context, leading sometimes to increased motivation [4]. These findings call for studies assessing the role of inflammation in different dimensions of fatigue, and how to measure these in both subjective and objective ways.

Fatigue – a multidimensional concept

Fatigue can be highly disabling. It is very common in various medical conditions (Table 1) and is associated with impaired quality of life, reduced social relationships, and reduced treatment adherence.

Role Inflammation Fatigue Table 1

Table 1. Prevalence of fatigue in various medical conditions.

But what is fatigue? Fatigue is not just fatigue. The feeling of fatigue actually involves different features (Figure 1) [10]. You can be physically tired, having difficulties performing activities; you can be mentally tired, struggling to concentrate and perform mental tasks; you can also lack motivation to perform physical or cognitive tasks and thus have the feeling of being tired. These dimensions of fatigue can be, and often are, associated. But they do not necessarily co-exist [11]. Hence, the involvement of each dimension in the overall feeling of fatigue can differ significantly from one condition to another and from one patient to another.

Role Inflammation Fatigue Figure 1Figure 1: Fatigue dimensions

The feeling of fatigue involving different features, i.e., physical fatigue, mental fatigue and lack of motivation, which are usually associated but not do necessarily coexist.

Importantly, these fatigue dimensions may involve distinct neuronal systems and would thus require specific treatments to relieve the feeling of fatigue. Research indicate that the feeling of mental fatigue derives from high cognitive load, reflected by increased activation of the anterior cingulate cortex, whereas the motivational dimension of fatigue more likely involves the mesolimbic reward system of the basal ganglia [1]. The “motor” pathway of the basal ganglia (nigrostriatal pathway) may instead be involved in the physical feeling of fatigue [1]. Moreover, we argue that increased sensitivity of the insular cortex to interoceptive signals may induce an overall feeling of fatigue [1]. As additional brain structures could also contribute to fatigue, studies assessing causes and outcomes in a multidimensional way are needed to better comprehend the neuronal mechanisms behind this debilitating state [10].

The understanding of fatigue is further complicated by the inaccurate common overlap between physiological and pathological fatigue. Fatigue is first and foremost an adaptive physiological process that signals the body to rest, in order to prevent injuries and avoid actions with a low cost-benefit balance [10, 12]. In some cases, however, the adaptive function is lost and fatigue instead becomes disabling (Figure 2) [13]. Because physiological fatigue is an adaptive process known by all humans, patients who instead suffer from pathological fatigue can encounter difficulties in making their social surroundings and caregivers, who have only experienced physiological, adaptive fatigue, understand the nature of their symptoms. This has been aptly described by MJ Poulson, in Journal of Clinical Oncology in 2001 [14]. Poulson was a 46-year-old palliative care physician who suffered from inflammatory breast cancer. She tried to describe her feeling of fatigue, the most overwhelming symptoms among her cancer-related symptoms, to her physician:

“- I [am] plagued by fatigue and lack of energy. I am feeling as if I can hardly put one foot in front of the other at times.

– I sure know how you feel, he said reassuringly. […] I didn’t stop all week. I still haven’t caught up yet. A day or two off would be so nice, wouldn’t it?

As I was that patient, I wanted to shake my doctor by the collar of his lab coat and scream. “No, that’s wrong! You have no idea how I feel!” But I did not have the energy.”

Because the same words are used to describe physiological and pathological fatigue, the latter is often misinterpreted [14]. We therefore need a better understanding of both physiological and pathological fatigue if we are to determine the factors turning fatigue into a dysfunctional process, and learn how to prevent and overturn this maladaptive fatigue (Figure 2). One such factor, hypothesized to play a role in turning physiological into pathological fatigue, is inflammation.

Figure 2: Physiological and pathological fatigue. Fatigue is an adaptive physiological process that signals the body to rest, and which is alleviated by rest and sleep. Fatigue can also develop into a dysfunctional, pathological process, which is not alleviated by rest or sleep.

 

Role Inflammation Fatigue Figure 2

Fatigue as an inflammation-induced symptom

One of the first and most common feelings associated with the activation of the immune system (e.g., during infection) is fatigue. When the immune system is activated, immune cells produce inflammatory cytokines that coordinate the fight against the pathogen. In addition to their peripheral effects, cytokines have the ability to act on the central nervous system and to induce a large array of behavioral alterations, collectively referred to as sickness behavior [15]. Sickness behavior is an adaptive process, allowing the body to redirect energy towards fighting the infection by reducing food consumption, physical activities, and social interactions [16]. Fatigue, being a strong signal to rest, is thus central in sickness behavior, and appears very sensitive to the effects of cytokines. This was notably highlighted in cancer and hepatitis C patients after the instauration of immunotherapy, which increases circulating cytokines and rapidly induces the development of fatigue in up to 80% of patients [9].

Inflammation has therefore been suggested as a potential contributor to the development of (pathological) fatigue. Increasing clinical evidence supports the role of inflammation in fatigue in patients suffering from medical conditions that are characterized by both high rates of fatigue and alterations in inflammatory processes, such as cancer survivors, and patients with multiple sclerosis or diabetes [7, 17, 18]. For instance, previous studies have shown a significant association between circulating levels of inflammatory markers and the intensity of fatigue in these clinical populations [19-21]. Importantly, inflammation has also been shown to modulate the activity of the brain structures believed to be involved in fatigue, such as basal ganglia [22, 23], the anterior cingulate cortex [24, 25] and the insula [26, 27].

Only a few studies have investigated the association between inflammation and fatigue in a multidimensional way [1]. Some studies in cancer patients and survivors indicate that physical, rather than mental, aspects of fatigue may be associated with inflammation [28, 29]. On the other hand, a study of type 2 diabetes found that increased levels of inflammatory markers relates particularly to mental fatigue and lack of motivation, but not to physical fatigue [20]. In multiple sclerosis, however, inflammation appears to affect several dimensions of fatigue [21]. Although these studies need replications in order to fully understand the role of inflammation in specific dimensions of fatigue in various medical conditions, they illustrate that inflammation does not necessarily relate to all dimensions of fatigue, and that other factors may also be involved. Importantly, these studies indicate that an “inflammation-specific type of fatigue” may not exist and that inflammation may rather affect different dimensions of fatigue in different medical conditions. This will need to be disentangled in future studies.

Inflammation induces motivational reorganization rather than loss of motivation

As mentioned earlier, loss of motivation appears as a core feature of fatigue – being able to produce a feeling of physical and/or mental fatigue. As such, it provides an important opportunity for understanding the role of inflammation in the development of fatigue. Motivation and motivated behavior also provide good examples for illustrating the importance of assessing the multidimensional aspects of fatigue in both subjective and objective ways. Indeed, subjective and objective fatigue have been found to not always correlate [30], indicating that they may represent distinct underlying concepts.

The common assumption of the motivational consequences of inflammation is loss of motivation, as sickness behavior includes decreased appetite, reduced activities, etc. Reduced motivation to perform activities that we usually like is indeed strongly associated with sickness. This is reflected in studies using experimental inflammation (e.g., experimentally activating the immune system using intravenous injection of a bacterial endotoxin), where individuals report an overall lack of interest [31], and exhibit reduced brain activity in the ventral striatum in response to monetary reward [32]. This notion was similarly suggested in earlier work in rodents, which showed reduced willingness to expend effort in order to obtain a reward (e.g., food) during experimental inflammation [33, 34].

However, the effect of inflammation on motivated behavior appears to be more complex [4]. Two recent studies published in Neuropsychopharmacology used objective tasks, similar to the effort-basted decision-making paradigms used in rodents, to assess the effect of experimental inflammation on motivated behavior in humans [2, 3]. Both studies showed that inflammation modulates incentive motivation (i.e., the willingness to expend effort) rather than reward sensitivity (i.e., liking of the reward). However, these two studies demonstrated opposite effects of inflammation on the willingness to expend effort in order to obtain a monetary reward. In one study, participants chose to perform fewer monetarily rewarding effortful tasks during experimental inflammation [3], and in the other, inflammation increased the willingness to expend effort in order to get a monetary reward when the probability to get the reward was high [2]. However, in the second study, participants could not choose to rest. They were instead put in a forced-choice condition between high effort/high reward and low effort/low reward tasks. In other words, when some effort was required, participants chose the task that was deemed worthwhile (i.e., with a high probability to get the reward), and even more so during experimental inflammation [2]. Interestingly, this result was in line with a previous study performed in mice, where experimental inflammation lead to proportionally choosing the high-effort, high-reward (chocolate) task more often than the low-effort, low-reward (grain) task [35]. Increased motivation has also been measured at the subjective level during inflammation, with people exhibiting higher motivation to be close to people that may provide care, such as a family member [36].

Altogether, these studies strengthen the notion that inflammation induces a reorganization of motivational priorities [37, 38]. This implies that motivational changes induced by inflammation depend on the nature and context of the task [4]. This is reflected in reduced motivation to perform tasks that could jeopardize the body while fighting infection or that can be postponed until the body has recovered, but also in increased motivation for comforting or caring rewards.

Conclusion

The role of inflammation in the development of pathological fatigue remains relevant but unclear. We argue for the need of multidimensional assessments as well as for a combination of subjective and objective measures to better comprehend the effects of inflammation on fatigue.

Authors Affiliation

Julie Lasselin1,2,3, Bianka Karshikoff3,4, Tina Sundelin3,5 1 Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, Essen, Germany; 2 Stress Research Institute, Stockholm University, Stockholm, Sweden; 3Department of Clinical Neuroscience, Division for Psychology, Karolinska Institutet, Stockholm, Sweden; 4 Department of Anesthesiology, Perioperative and Pain Medicine, Division of Pain Medicine, Stanford University School of Medicine, Palo Alto, USA; 5 Department of Psychology, New York University, New York, USA;

Contacts: Julie Lasselin, Stress Research Institute, Stockholm University, SE-106 91 Stockholm, Sweden; email: julie.lasselin@su.se

References

1          Karshikoff B, Sundelin T, Lasselin J. Role of Inflammation in Human Fatigue: Relevance of Multidimensional Assessments and Potential Neuronal Mechanisms. Front Immunol 2017; 8: 21.

2          Lasselin J, Treadway MT, Lacourt TE, et al. Lipopolysaccharide Alters Motivated Behavior in a Monetary Reward Task: a Randomized Trial. Neuropsychopharmacology 2017; 42: 801-10.

3          Draper A, Koch RM, van der Meer JW, Aj Apps M, Pickkers P, Husain M, van der Schaaf ME. Effort but not Reward Sensitivity is Altered by Acute Sickness Induced by Experimental Endotoxemia in Humans. Neuropsychopharmacology 2017.

4          Irwin MR, Eisenberger NI. Context-Dependent Effects of Inflammation: Reduced Reward Responding is Not an Invariant Outcome of Sickness. Neuropsychopharmacology 2017; 42: 785-6.

5          Kroenke K, Wood DR, Mangelsdorff AD, Meier NJ, Powell JB. Chronic fatigue in primary care. Prevalence, patient characteristics, and outcome. JAMA 1988; 260: 929-34.

6          Kroenke K, Stump T, Clark DO, Callahan CM, McDonald CJ. Symptoms in hospitalized patients: outcome and satisfaction with care. Am J Med 1999; 107: 425-31.

7          Lasselin J, Capuron L. Chronic low-grade inflammation in metabolic disorders: relevance for behavioral symptoms. Neuroimmunomodulation 2014; 21: 95-101.

8          Weiland TJ, Jelinek GA, Marck CH, Hadgkiss EJ, van der Meer DM, Pereira NG, Taylor KL. Clinically significant fatigue: prevalence and associated factors in an international sample of adults with multiple sclerosis recruited via the internet. PLoS One 2015; 10: e0115541.

9          Capuron L, Miller AH. Cytokines and psychopathology: lessons from interferon-alpha. Biol Psychiatry 2004; 56: 819-24.

10        DeLuca J. Fatigue as a window to the brain. The MIT Press. 2005.

11        Smets EM, Garssen B, Bonke B, De Haes JC. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995; 39: 315-25.

12        Boksem MA, Tops M. Mental fatigue: costs and benefits. Brain research reviews 2008; 59: 125-39.

13        Chaudhuri A, Behan PO. Fatigue in neurological disorders. Lancet 2004; 363: 978-88.

14        Poulson MJ. Not just tired. J Clin Oncol 2001; 19: 4180-1.

15        Dantzer R. Cytokine-induced sickness behavior: where do we stand? Brain Behav Immun 2001; 15: 7-24.

16        Hart BL. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 1988; 12: 123-37.

17        Klimas NG, Broderick G, Fletcher MA. Biomarkers for chronic fatigue. Brain Behav Immun 2012; 26: 1202-10.

18        Bower JE, Lamkin DM. Inflammation and cancer-related fatigue: mechanisms, contributing factors, and treatment implications. Brain Behav Immun 2013; 30 Suppl: S48-57.

19        Orre IJ, Reinertsen KV, Aukrust P, Dahl AA, Fossa SD, Ueland T, Murison R. Higher levels of fatigue are associated with higher CRP levels in disease-free breast cancer survivors. J Psychosom Res 2011; 71: 136-41.

20        Lasselin J, Laye S, Dexpert S, Aubert A, Gonzalez C, Gin H, Capuron L. Fatigue symptoms relate to systemic inflammation in patients with type 2 diabetes. Brain Behav Immun 2012; 26: 1211-9.

21        Heesen C, Nawrath L, Reich C, Bauer N, Schulz KH, Gold SM. Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour? J Neurol Neurosurg Psychiatry 2006; 77: 34-9.

22        Felger JC, Miller AH. Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise. Front Neuroendocrinol 2012; 33: 315-27.

23        Dowell NG, Cooper EA, Tibble J, Voon V, Critchley HD, Cercignani M, Harrison NA. Acute Changes in Striatal Microstructure Predict the Development of Interferon-Alpha Induced Fatigue. Biol Psychiatry 2016; 79: 320-8.

24        Capuron L, Pagnoni G, Demetrashvili M, Woolwine BJ, Nemeroff CB, Berns GS, Miller AH. Anterior cingulate activation and error processing during interferon-alpha treatment. Biol Psychiatry 2005; 58: 190-6.

25        Hannestad J, Subramanyam K, Dellagioia N, Planeta-Wilson B, Weinzimmer D, Pittman B, Carson RE. Glucose metabolism in the insula and cingulate is affected by systemic inflammation in humans. J Nucl Med 2012; 53: 601-7.

26        Lekander M, Karshikoff B, Johansson E, et al. Intrinsic functional connectivity of insular cortex and symptoms of sickness during acute experimental inflammation. Brain Behav Immun 2016; 56: 34-41.

27        Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Dolan RJ, Critchley HD. Neural origins of human sickness in interoceptive responses to inflammation. Biol Psychiatry 2009; 66: 415-22.

28        Orre IJ, Murison R, Dahl AA, Ueland T, Aukrust P, Fossa SD. Levels of circulating interleukin-1 receptor antagonist and C-reactive protein in long-term survivors of testicular cancer with chronic cancer-related fatigue. Brain Behav Immun 2009; 23: 868-74.

29        de Raaf PJ, Sleijfer S, Lamers CH, Jager A, Gratama JW, van der Rijt CC. Inflammation and fatigue dimensions in advanced cancer patients and cancer survivors: an explorative study. Cancer 2012; 118: 6005-11.

30        Leavitt VM, DeLuca J. Central fatigue: issues related to cognition, mood and behavior, and psychiatric diagnoses. PM & R : the journal of injury, function, and rehabilitation 2010; 2: 332-7.

31        DellaGioia N, Devine L, Pittman B, Hannestad J. Bupropion pre-treatment of endotoxin-induced depressive symptoms. Brain Behav Immun 2013; 31: 197-204.

32        Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, Irwin MR. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry 2010; 68: 748-54.

33        Merali Z, Brennan K, Brau P, Anisman H. Dissociating anorexia and anhedonia elicited by interleukin-1beta: antidepressant and gender effects on responding for “free chow” and “earned” sucrose intake. Psychopharmacology (Berl) 2003; 165: 413-8.

34        Nunes EJ, Randall PA, Estrada A, et al. Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/ chow feeding choice task. Psychopharmacology (Berl) 2014; 231: 727-36.

35        Vichaya EG, Hunt SC, Dantzer R. Lipopolysaccharide reduces incentive motivation while boosting preference for high reward in mice. Neuropsychopharmacology 2014; 39: 2884-90.

36        Inagaki TK, Muscatell KA, Irwin MR, et al. The role of the ventral striatum in inflammatory-induced approach toward support figures. Brain Behav Immun 2015; 44: 247-52.

37        Aubert A, Goodall G, Dantzer R, Gheusi G. Differential effects of lipopolysaccharide on pup retrieving and nest building in lactating mice. Brain Behav Immun 1997; 11: 107-18.

38        Larson SJ. Behavioral and motivational effects of immune-system activation. J Gen Psychol 2002; 129: 401-14.


Related stories you may like: High Blood Interferon-γ Levels Linked to the Early Phase of Chronic Fatigue Syndrome
Deficiency of IL-10 in Chronic Fatigue Syndrome?
The selfishness of the brain and immune systems provoke energy deficiency in aging and chronic inflammation
Evolutionary Medicine, Energy Regulation and the Pathogenesis of Systemic Chronic Inflammatory Diseases

 

The post Understanding the Role of Inflammation in Fatigue Requires Multidimensional Assessments appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
5905
First Evidence that Catecholamines Inhibit IL-27 Production by Antigen Presenting Cells http://www.brainimmune.com/catecholamines-inhibit-il-27-production/ Sat, 06 Jan 2018 13:13:06 +0000 http://www.brainimmune.com/?p=5895 A recent J. Immunology study provides perhaps the first evidence that catecholamines such as norepinephrine and epinephrine suppress the production of interleukin-27 (IL-27) via the activation of β2-adrenoceptors, and by mechanisms involving IL-10 and the JNK signaling pathway. Homeostasis within the immune system is largely dependent on cytokines, the ‘hormones’ of the immune system that […]

The post First Evidence that Catecholamines Inhibit IL-27 Production by Antigen Presenting Cells appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
A recent J. Immunology study provides perhaps the first evidence that catecholamines such as norepinephrine and epinephrine suppress the production of interleukin-27 (IL-27) via the activation of β2-adrenoceptors, and by mechanisms involving IL-10 and the JNK signaling pathway.

Homeostasis within the immune system is largely dependent on cytokines, the ‘hormones’ of the immune system that control immune and inflammatory responses. Immunogenetic and neurohormonal mechanisms are known to influence cytokine profiles and production.

The neurohormonal control is exerted by the neuroendocrine humoral outflow via the pituitary and the autonomic nervous system (ANS) via direct neuronal influences. The sympathetic nervous system (SNS), a major part of the ANS, innervates all primary and secondary lymphoid organs. The catecholamines such as norepinephrine (noradrenaline), epinephrine (adrenaline) and dopamine, along with NPY and ATP represent the major SNS neuromediators and neurotransmitters.

IL-27, a cytokine identified in 2002, is a member of the IL-12 and IL-6 cytokine families, and the group of dimer cytokines that include IL-12, IL-23 and IL-35. It consists of the signature subunit p28 (IL-27p28), and a second subunit, the EBV-induced gene 3 (EBI3), which is shared with heterodimeric IL-35 (EBI3/p35).

IL-27 displays pleiotropic functions involving immune-enhancing, immune-regulatory and anti-inflammatory effects.

The immune-enhancing activities of IL-27 include the promotion of clonal expansion of naïve CD4+ T cells, and the IL-27 mediated Th1 polarization and IFN- production in naïve CD4+ T cells. On the other hand, IL-27 has anti-inflammatory and immune-regulatory functions and inhibits Th2, innate lymphoid cell-2 (ILC2), and Th17 responses. Importantly, IL-27 stimulates CD4+ T cells to express the immuneregulatory and anti-inflammatory cytokine IL-10.

In general, IL-27 promotes the differentiation of Th1 and Tr1 cells, but inhibits the differentiation of Th2, Th17, and Treg cells.

In the J. Immunology study, Julian Roewe and colleagues from the University Medical Center, Johannes Gutenberg University Mainz in Germany demonstrate that the catecholamines norepinephrine (noradrenaline) and epinephrine (adrenaline) are able to inhibit the IL-27 release by LPS/TLR4-activated macrophages.

This is achieved by the stimulation of β2-adrenoceptors expressed on these cells. This effect appears to be dependent on an inhibitory feedback loop related to IL-10. Importantly, β2-adrenoceptors agonists in combination with IL-10 down-regulate the IL-27–stimulating intracellular JNK signaling pathway.

The authors discuss that the “fine-tuning of IL-27–dependent immune responses by catecholamines presumably relays multilayered context-dependent influences on the prevailing inflammatory states”.

Furthermore, as IL-27 has been suggested as a biomarker for the diagnosis of sepsis patients, according to the authors, the catecholamine therapy often used in this condition, may in fact represent a confounding factor and may distort IL-27 concentrations.

Thus, future studies related to the functional consequences and the implications of the above-described observations, are warranted.

Source: J Immunol, 2017, 199(7):2503-2514. doi: 10.4049/jimmunol.1700687. Epub 2017 Aug 23.
Read More: J. Immunology


Further Readings: The sympathetic nerve–an integrative interface between two supersystems: the brain and the immune system
Adrenergic modulation of dendritic cells function: relevance for the immune homeostasis
Sympathetic neural-immune interactions regulate hematopoiesis, thermoregulation and inflammation in mammals


Related stories you may like: Activation of Beta2-Adrenoreceptors Drives T Helper Cell Priming In Favor of IL-17 Responses
Beta-Adrenoceptors and Tumor Development: Novel Concepts and Clinical Implications
Sympathetic Nerves via β2-adrenoceptor Signaling Generate Circadian Rhythms and Govern Lymphocyte Recirculation
Endogenous Catecholamines in Immune Cells: Discovery, Functions And Clinical Potential as Therapeutic Targets

The post First Evidence that Catecholamines Inhibit IL-27 Production by Antigen Presenting Cells appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
5895
First Evidence that Macrophages Modulate Heart Electrical Conduction System http://www.brainimmune.com/macrophages-modulate-heart-electrical-conduction/ Mon, 04 Dec 2017 18:23:46 +0000 http://www.brainimmune.com/?p=5847 In a recent Cell study, Maarten Hulsmans et al. report the presence of abundant resident macrophages in the heart atrioventricular (AV) node, and provide first evidence that these cells modulate the electrical conduction and activity of cardiomyocytes. This phenomenon may be related to the pathogenic electrical conduction in heart conditions such as atrial fibrillation and […]

The post First Evidence that Macrophages Modulate Heart Electrical Conduction System appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
In a recent Cell study, Maarten Hulsmans et al. report the presence of abundant resident macrophages in the heart atrioventricular (AV) node, and provide first evidence that these cells modulate the electrical conduction and activity of cardiomyocytes. This phenomenon may be related to the pathogenic electrical conduction in heart conditions such as atrial fibrillation and ventricular arrhythmias.

The heart rhythm is controlled by electrical impulses generated in the sinoatrial node that propagates towards the atrium, AV node, His and Purkinje systems and ventricles. The AV node is composed by cardiomyocytes and plays an essential role in conducting electrical impulses between atria and ventricles. Of note, AV abnormalities (AV blocks) are serious life threatening conditions, and pacemaker implantation is essential to restore node conductibility.

Macrophages (Mφ) are found in all body tissues and are classically known for their involvement in immune homeostasis and inflammation control. In the heart, Mφ are distributed along with myocytes, fibroblasts and endothelial cells, but their role in cardiac activity is unknown.

In the Cell  study, the multicentre, multinational team from the US, Ireland, Germany France and the UK, firstly identified the precise morphology and location of cardiac macrophages in Cx3Cr1GFP/+ mice, which express the GFP protein in Mφ. Cardiac Cx3Cr1GFP/+ Mφ are located mostly in the AV node and neural bundle and have an elongated morphology with far-reaching cytoplasmatic projections.

The authors also showed that these Mφ express ion channels and exchangers, and genes associated to electrical conduction. In addition, these cells interact with cardiomyocytes through gap juntion proteins (connexin 43) that mediate intercellular communication and influence cardiomyocytes’ resting potential. In fact, Mφ increase cardiomyocyte resting membrane potentials, suggesting their role in cardiomyocyte repolarization.

When optogenetics are employed to photostimulate AV Mφ, cyclical Mφ depolarization modulated cardiomyocytes activity and improved AV nodal conduction. On the other side, congenital lack of Mφ, acute Mφ depletion or connexin 43 KO mice presented similar clinical features of cardiac electrical conduction pathologies, as prolongation in PR (AV block) and AH (delayed conduction from AV node to the His bundle) intervals, demonstrating impaired AV conduction.

The authors discuss that conditions such as myocardial infarction, heart failure and diabetes or inflammatory diseases of the heart such as Chagas, Lyme, sarcoid, and myocarditis are related to changes in macrophages’ phenotype and numbers, which in turn may contribute to arrhythmias and conduction abnormalities.

According to the authors this new pathophysiologic role of AV Mφ may also suggest novel therapeutic strategies focusing on AV Mφ activity.

Source: Cell, 2017. 169(3): 510-522 18. doi: 10.1016/j.cell.2017.03.050
Read more: Cell


Related story you may like:
Innate Immune Cells’ Network the Cardio-Splenic Axis and Heart Failure
β2-Adrenergic Receptor Activation Promotes M2 Polarization of Gut Macrophages
Stress-Mediated M2 Macrophage Polarization Promoting Tumor Growth
2017 in Review: New Advances in Neuroendocrine Immunology

The post First Evidence that Macrophages Modulate Heart Electrical Conduction System appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

]]>
5847