BrainImmune: Trends in Neuroendocrine Immunology http://www.brainimmune.com New concepts & viewpoints in brain–immune interactions, stress and immunity, the interface of neuroscience & immunology on BrainImmune Mon, 15 Oct 2018 16:38:42 +0000 en-US hourly 1 Glucocorticoid Signaling: From Molecules to Mice to Man http://www.brainimmune.com/glucocorticoid-signaling-book/ Mon, 15 Oct 2018 12:24:27 +0000 http://www.brainimmune.com/?p=6407 Glucocorticoid Signaling: From Molecules to Mice to Man (Advances in Experimental Medicine and Biology) is published by Springer; 1st ed. 2015 edition, and edited by Jen-Chywan Wang and Charles Harris. Glucocorticoids, the steroid hormones secreted from the zona fasciculata of the adrenal cortex, play an important role in the maintenance of internal homeostasis by influencing […]

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Glucocorticoid SignalingGlucocorticoid Signaling: From Molecules to Mice to Man (Advances in Experimental Medicine and Biology) is published by Springer; 1st ed. 2015 edition, and edited by Jen-Chywan Wang and Charles Harris.

Glucocorticoids, the steroid hormones secreted from the zona fasciculata of the adrenal cortex, play an important role in the maintenance of internal homeostasis by influencing activities of virtually all organs and tissues, such as the brain, liver, skeletal muscles and the immune-related organs and cells

Glucocorticoid Signaling: From Molecules to Mice to Man provides a comprehensive overview of glucocorticoids and their role in regulating many aspects of physiology and their use in the treatment of disease.

The book is broken into four sections that begin by giving a general introduction to glucocorticoids and a brief history of the field. The second section discusses the effects of glucocorticoids on metabolism, while the third section covers the effects of glucocorticoids on key tissues.

The final section addresses general topics, such as animal models in glucocorticoid research and clinical implications of glucocorticoid research. Featuring chapters from leaders in the field, this volume is of interest to both researchers and clinicians.

Some chapters are listed below:

  • Regulatory Actions of Glucocorticoid Hormones: From Organisms to Mechanisms
  • Molecular Biology of Glucocorticoid Signaling
  • Clinical Perspective: What Do Addison and Cushing Tell Us About Glucocorticoid Action?
  • How Do Glucocorticoids Regulate Lipid Metabolism?
  • Glucocorticoids and Skeletal Muscle
  • Glucocorticoid-Induced Osteoporosis
  • Effects of Glucocorticoids in the Immune System
  • Glucocorticoids and the Brain: Neural Mechanisms Regulating the Stress Response
  • Glucocorticoid Regulation of Reproduction
  • Glucocorticoids and the Lung
  • Glucocorticoids and the Cardiovascular System
  • Glucocorticoids and Cancer
  • Animal Models of Altered Glucocorticoid Signaling

Series: Advances in Experimental Medicine and Biology (Book 872); Hardcover: 385 pages; Publisher: Springer; 1st ed. 2015 edition (July 28, 2015)

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Hormone Imbalance Syndrome: America’s Silent Plague http://www.brainimmune.com/hormone-imbalance-syndrome-book/ Mon, 15 Oct 2018 09:33:50 +0000 http://www.brainimmune.com/?p=6404 The Hormone Imbalance Syndrome is written by Benoit Tano, M.D., Ph.D and published by Integrative Medical Press (IMP). Obesity is the number one killer in the United States and, increasingly, the world. It kills in silence and indirectly, standing as the root cause of a great many of the diseases treated by healthcare providers, including […]

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Hormone Imbalance Syndrome America's Silent PlagueThe Hormone Imbalance Syndrome is written by Benoit Tano, M.D., Ph.D and published by Integrative Medical Press (IMP).

Obesity is the number one killer in the United States and, increasingly, the world. It kills in silence and indirectly, standing as the root cause of a great many of the diseases treated by healthcare providers, including hyperlipidemia, heart disease, diabetes, hypertension, and malignant tumors, to name only a few. If any other epidemic had caused as many deaths as obesity and its comorbidities, the whole world would be diligently searching for a cure.

Yet most healthcare providers take a surprisingly casual attitude toward obesity. In most cases, it is treated as a more or less benign condition easily dealt with if patients would only put forth some effort. This is to say that obesity is often treated as if it were the patient’s fault, with healthcare providers frequently assuming that a patient’s obesity is the result of poor dietary choices and sedentary lifestyle. The root cause of the obesity epidemic is neither explored nor serious weight loss treatment plans offered.

Hormone Imbalance Syndrome:America’s Silent Plague: Uncovering the Roots of the Obesity Epidemic and Most Common Diseases by Benoît Tano uses the CDC obesity maps, the US Geological Survey pesticides/herbicides maps, and Healthcare Cost and Utilization Project (HCUP) hospital and Emergency Department (ED) discharges data, to explore the origins of the growing obesity epidemic in the US.

Find out how pesticides/herbicides sprayed in farmlands and common household chemicals cause endocrine disruption (hormone imbalance) that leads to obesity and its comorbidities. This book, drawn from Dr. Tano’s research and clinical experience as an allergist and integrated health care practitioner, reveals the mechanisms behind the growing obesity epidemic and what to do about it.

Paperback: 520 pages; Publisher: Integrative Medical Press (IMP) (January 5, 2012)

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Sex Hormones and Immunity to Infection http://www.brainimmune.com/sex-hormones-immunity-infection-book/ Fri, 12 Oct 2018 10:45:07 +0000 http://www.brainimmune.com/?p=6401 Sex Hormones and Immunity to Infection, edited by Sabra L. Klein and Craig Roberts and published by Springer, critically reviews the evolutionary origin and the functional mechanisms responsible for sexual dimorphism in response to infection. Recent research suggests that sex hormones regulate immune responses in vivo. Thus, estrogens and testosterone regulate humoral immune responses i.e. […]

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Sex Hormones Immunity to InfectionSex Hormones and Immunity to Infection, edited by Sabra L. Klein and Craig Roberts and published by Springer, critically reviews the evolutionary origin and the functional mechanisms responsible for sexual dimorphism in response to infection.

Recent research suggests that sex hormones regulate immune responses in vivo. Thus, estrogens and testosterone regulate humoral immune responses i.e. (auto)antibody production; where estrogen increases, while testosterone decreases antibody production. Sex hormones also regulate cellular immunity, by affecting T lymphocytes, including T cell proliferation and cytotoxicity and T helper(Th) 1 and Th2 cellular responses.

In contrast to autoimmunity where females display an increased incidence of autoimmune diseases, the prevalence and intensity of infection typically is higher in males than females and may reflect differences in exposure as well as susceptibility to pathogens. Elevated immunity among females is a double-edged sword in which it is beneficial against infectious diseases but is detrimental in terms of increased development of autoimmune diseases.

The book emphasizes the value of examining responses in both males and females to improve our understanding about host-pathogen interactions in both sexes. Sex Hormones and Immunity to Infection aims at bringing insight to the treatment and management of infectious diseases; it delineates areas where knowledge is lacking and highlights future avenues of research.

The contributors of Sex Hormones and Immunity to Infection are experts in their specific disciplines which range from microbiology and immunology to genetics, pathology, and evolutionary biology.

Chapters:

  • Sex Differences in Susceptibility to Infection: An Evolutionary Perspective
  • Effects of Sex Steroids on Innate and Adaptive Immunity
  • Sex Steroid Receptors in Immune Cells
  • Sex Differences in Susceptibility to Viral Infection
  • Sex Differences in Innate Immune Responses to Bacterial Pathogens
  • Sex Hormones and Regulation of Host Responses Against Parasites
  • Sex Differences in Parasitic Infections: Beyond the Dogma of Female-Biased Resistance
  • Progesterone, Pregnancy, and Innate Immunity
  • Pregnancy and Susceptibility to Parasites
  • Sex Steroids and Risk of Female Genital Tract Infection
  • Sex, Pregnancy and Measles

Hardcover: 332 pages; Publisher: Springer; 2010 ed. edition (13 Nov. 2009)

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The Wisdom of the Body http://www.brainimmune.com/wisdom-of-the-body-book/ Thu, 11 Oct 2018 09:48:45 +0000 http://www.brainimmune.com/?p=6395 The Wisdom of the Body, the revised and enlarged edition was published by W. W. Norton & Company (April 17, 1963, shown on the left) but the first, original version was published in 1932, once again by W.W. Norton & Company (shown on the right). This classic medical book was written by Walter Cannon, an […]

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The Wisdom of the Body BrainImmuneThe Wisdom of the Body, the revised and enlarged edition was published by W. W. Norton & Company (April 17, 1963, shown on the left) but the first, original version was published in 1932, once again by W.W. Norton & Company (shown on the right). This classic medical book was written by Walter Cannon, an American physician-scientist and physiologist, who introduced the concepts of homeostasis, fight-or-flight responses, and the sympathoadrenal system.

In The Wisdom of the Body, the dynamic equilibrium/steady state of the internal milieu or homeostasis is the central theme and Walter Cannon popularized this new term in his book.

According to Cannon when the body’s homeostasis is threaten the sympathoadrenal system is activated The result of such stimulation is an increase in heart rate, constriction of blood vessels, and dilation of bronchioles and pupils, which allows the aroused organism to confront or flee the danger – the response, which is now well-known known as the fight-or-flight response. Cannon believed that the sympathoadrenal system plays a key role in returning the body to its normal state of equilibrium after such arousal had occurred.

Reviews:

“Cannon’s writing is clear and yet detailed, easily accessible to scientists and the lay public alike, and current findings and concepts of the time are summarized elegantly. His overarching point is that the human, characteristic of all mammals, relies less on an attempt to match his physiology with the external environment than to regulate his internal environment within narrow limits.

What Bernard refers to as the milieu interieur, Cannon calls the “fluid matrix.” Discussing how this fluid matrix and its integrity is maintained, he reviews current research, his own and others’, in the areas of thirst and hunger, water content of the blood, salt content, blood sugar/proteins/fat/calcium, oxygen supply, ph neutrality, and body temperature.

The Wisdom of the Body cover 1932He also discusses the aging of homeostatic mechanisms over time before embarking on natural defenses of the organism and the margin of safety in bodily structures and function. His penultimate subject is “the two grand divisions of the nervous system” with particular attention to the role of the sympathetic (“sympathico-adrenal”) nervous system in homeostasis. After summarizing this entire discussion, Cannon provides a brief epilogue exploring possible relationships or parallels between biological and social homeostasis, an exploration heavily influenced by social theory of his time.

This is a fascinating and articulate presentation of fundamental understandings of human biology that have provided the foundation for subsequent medical research over the past eighty years.”

– Bruce, goodreads.com

Paperback: 340 pages; Publisher: W. W. Norton & Company; Rev. and Enl. Ed edition (April 17, 1963)

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Neuroimmune pharmacology 2nd edition http://www.brainimmune.com/neuroimmune-pharmacology-book/ Wed, 10 Oct 2018 11:30:55 +0000 http://www.brainimmune.com/?p=6391 Neuroimmune pharmacology is a relatively new discipline, however well-grounded on interdisciplinary basic and translational research in pharmacology, immunology and neuroscience, aiming at the therapeutic exploitation of the rapidly growing knowledge about physiology and pathology of nervous system-immune system interconnections. The Society on Neuroimmune Pharmacology was founded in1993, while the first issue of the Journal of […]

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Neuroimmune Pharmacology 2nd EditionNeuroimmune pharmacology is a relatively new discipline, however well-grounded on interdisciplinary basic and translational research in pharmacology, immunology and neuroscience, aiming at the therapeutic exploitation of the rapidly growing knowledge about physiology and pathology of nervous system-immune system interconnections.

The Society on Neuroimmune Pharmacology was founded in1993, while the first issue of the Journal of Neuroimmune Pharmacology was published in March 2006.

The 2nd edition of Neuroimmune Pharmacology by Howard E. Gendelman and Tsuneya Ikezu (Editors) with Serge Przedborski, Eliezer Masliah and Marco Cosentino (Associate Editors) has been published in 2017, nearly 9 years after the 1st edition.

With more than one thousand pages (two hundred pages more than the previous edition), Neuroimmune Pharmacology provides a comprehensive and cutting edge picture of the tremendous progresses achieved in the understanding of the mutual interconnections among inflammation, immunity and neural control of disease, in the central nervous system as well as in periphery.

Take just Parkinson’s disease (PD) as an example. Up to only a few years ago, investigating the role of inflammation and peripheral immunity in PD would have been considered unreasonable by most neuroscientists and immunologists. At present however PD-associated neurodegeneration as a consequence of neuroinflammation in turn supported by peripheral T cells likely activated by peripheral leakage of a-synuclein is much more than a simple speculation, and innovative therapeutics targeting inflammation and immunity increasingly represent promising opportunities for PD patients.

New developments in PD, as well as in multiple sclerosis, Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, prion disease, HIV, drugs of abuse, autism spectrum disorders and many others are extensively discussed together with novel and emerging therapeutic strategies, including immunotherapies for neurodegenerative disorders, polymer nanomaterials for drug delivery in the central nervous system, gene therapy and vaccination.

With 56 chapters authored by prominent experts in their respective fields, Neuroimmune Pharmacology is organized into three parts, dedicated to Immunology of the Nervous System, Immunology of Neurodegenerative, Neuroinflammatory, Neuroinfectious and Neuropsychiatric Disorders, and Therapies and Diagnostics.

As a whole, the book is a standalone reference for preclinical and clinical researchers as well as for clinicians searching for a guidance into the rapidly developing interdisciplinary field of neuroimmune pharmacology.

Publisher: Springer; 2nd ed. 2017 edition (December 23, 2016); Hardcover: 1035 pages – ISBN 978-3-319-44020-0; eBook: ISBN 978-3-319-44022-4

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Rethinking Homeostasis: Allostatic Regulation in Physiology and Pathophysiology http://www.brainimmune.com/rethinking-homeostasis-book/ Wed, 10 Oct 2018 11:21:42 +0000 http://www.brainimmune.com/?p=6388 Rethinking Homeostasis: Allostatic Regulation in Physiology and Pathophysiology is published by A Bradford Book and authored by Jay Schulkin Homeostasis as a concept and term was introduced by the American physiologist WalterCannon and refers to the stability of the inner world, or the various bodily states that make up the internal environment. Examples include for […]

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Rethinking Homeostasis Allostatic Regulation PhysiologyRethinking Homeostasis: Allostatic Regulation in Physiology and Pathophysiology is published by A Bradford Book and authored by Jay Schulkin

Homeostasis as a concept and term was introduced by the American physiologist WalterCannon and refers to the stability of the inner world, or the various bodily states that make up the internal environment. Examples include for example temperature regulation and oxygen consumption Homeostasis, was a direct extension from Claude Bernards of the milieu intérieur.

According to Cannon, the brain coordinates body systems, with the aim of maintaining a set of goal values for key internal variables. Internal or external disturbances threatening homeostasis, by causing large enough deviations from the goal values, arouse internal nervous and hormone systems, induce emotional and motivational states, and generate externally observable behaviors, all of which have the goal of reestablishing homeostasis. According to the more recent concept of allostasis, however, no single set of ideal values exists for levels of internal variables.

When an organism is under stress, the central nervous system works with the endocrine system to use resources to maintain the overall viability of the organism. The process accelerates the various systems’ defenses of bodily viability, but can violate short-term homeostasis. This allostatic regulation highlights our ability to anticipate, adapt to, and cope with impending future events.

Rethinking Homeostasis focuses on the concept of motivation and its relationship to the central nervous system function and specific hormonal systems. Schulkin applies a neuroendocrine perspective to central motive states such as cravings for water, sodium, food, sex, and drugs. He examines in detail the bodily consequences of the behavioral and neuroendocrine regulation of fear and adversity, the endocrine regulation of normal and preterm birth, and the effects of drug addiction on the body. Schulkin’s presentation of allostasis lays the foundation for further study.

Book’s chapters are listed below: Contents:

  1. Allostasis: The Emergence of a Concept
  2. Central Motive States: Feedforward Neuroendocrine Systems in the Brain
  3. Anticipation, Angst, Allostatic Regulation: Adrenal Steroid Regulation of Corticotropin-Releasing Hormone
  4. Normal and Pathological Facilitation of Parturition by a Feedforward Endocrine Mechanism
  5. Addiction to Drugs: Allostatic Regulation under Duress

Series: MIT Press Hardcover: 288 pages; Publisher: A Bradford Book (January 31, 2003)

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Pain and Neuroimmune Interactions http://www.brainimmune.com/pain-neuroimmune-interactions-book/ Tue, 09 Oct 2018 09:54:23 +0000 http://www.brainimmune.com/?p=6385 Pain and Neuroimmune Interactions is published by Springer and edited by Nayef E. Saade, Nayef E. Saadé, Suhayl J. Jabbur and A. Vania Apkarian. Pain is a product of various pathways and mechanisms within the nervous system in response to inflammation or trauma. Over 1.5 billion people suffer from chronic pain with 3-4.5% of the […]

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Pain and Neuroimmune InteractionsPain and Neuroimmune Interactions is published by Springer and edited by Nayef E. Saade, Nayef E. Saadé, Suhayl J. Jabbur and A. Vania Apkarian.

Pain is a product of various pathways and mechanisms within the nervous system in response to inflammation or trauma. Over 1.5 billion people suffer from chronic pain with 3-4.5% of the global population suffering specifically from neuropathic pain, and the incidence is increasing complementary to age.

Recent research indicates that the sensation of pain and suffering could be considered as part of a mechanism that involves not only sizeable areas in the brain but also simultaneous activations of the immune and the endocrine systems as well.

An increasing body of evidence suggests that pain involves different neural, immune and endocrine mechanisms that interact at peripheral and central levels. Furthermore, chronic pain could then be looked upon as a corollary of the imbalance in the cross talk between these systems, which could lead to new treatment strategies.

The aim of this book is not to deal with acute pain that serves as an alarm signal, but to attempt to explain the molecular mechanisms of chronic pain considered as a multifactorial syndrome or disease.

The chapters of this book are shown below:

  • Nociceptor Excitation by Sensitization: A Novel Hypothesis, Its Cellular and Molecular Background by Reeh, Peter W. (et al.)
  • Tachykinins in Visceral Pain and Hyperalgesia by Cervero, Fernando (et al.)
  • Bradykinin, Cytokines and Inflammatory Hyperalgesia by Poole, Stephen (et al.)
  • Neurotransmitter and Inflammatory Correlates in Experimental Neuropathy: Modulation by Electric Spinal Cord Stimulation by Linderoth, Bengt (et al.)
  • Diffuse Noxious Inhibitory Controls and Arthritis in the Rat by Danziger, Nicolas (et al.)
  • NSAIDs and Some Safe Strategies of Their Use: Spinal C-Fos Protein Studies in Carrageenan Model of Inflammatory Nociceptive Processes by Buritova, Jaroslava (et al.)
  • The Role of Dorsal Root Reflexes in Neurogenic Inflammation and Pain by Willis, William D. (et al.)
  • Pain and Neurogenic Inflammation: A Neural Substrate for Neuroendocrine-Immune Interactions by Saadé, Nayef E. (et al.)
  • Thymic Peptides: Transmitters Between the Neuroendocrine and the Immune System by Dardenne, Mireille (et al.)
  • Thymulin and Inflammatory Pain: A Possible Substrate for Pge-2 Dependent Neuroimmune Loop by Safieh-Garabedian, Bared (et al.)
  • The Role of Peripheral and Brain-Borne Cytokines in Immune-Neuro-Endocrine Interactions by Besedovsky, Hugo O. (et al.)
  • Interleukin-1 Receptors and Ligands in the Nervous System by Haour, France (et al.)
  • Biphasic Modulation of Pain by Hypothalamic Cytokines by Hori, T. (et al.)
  • In Search of Pain Consciousness or Pain and the Metaphysics of a Porsche 911 by Apkarian, A. Vania
  • How Do Strokes Cause Pain? by Tasker, Ronald R.
  • Chronic Pain: Somatic or Limbic Mechanisms by Jabbur, Suhayl J. (et al.)
  • Where Would One Seek Links Between the Nervous and Immune Systems? by Wall, Patrick D.

Hardcover: 244 pages; Publisher: Springer; 2000 edition (April 30, 2000)

Related stories you may like: Brain TNF and chronic pain
Brain TNF as therapeutic target for chronic pain
Microglia and neuropathic pain

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Immunoendocrinology: Scientific and Clinical Aspects http://www.brainimmune.com/immunoendocrinology-aspects/ Sun, 07 Oct 2018 11:28:13 +0000 http://www.brainimmune.com/?p=6382 Immunoendocrinology: Scientific and Clinical Aspects is published by Humana Press and edited by George S. Eisenbarth. The book is focused on autoimmune disorders, and particularly, endocrine autoimmune diseases. With the exception of celiac disease, the environmental factors that contribute to the onset, development and the marked increase in many of these disorders remain poorly understood. […]

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mmunoendocrinology AspectsImmunoendocrinology: Scientific and Clinical Aspects is published by Humana Press and edited by George S. Eisenbarth.

The book is focused on autoimmune disorders, and particularly, endocrine autoimmune diseases. With the exception of celiac disease, the environmental factors that contribute to the onset, development and the marked increase in many of these disorders remain poorly understood.

Immunoendocrinology: Scientific and Clinical Aspects outlines the central role of immune-endocrinologic processes in the pathogenesis of not only type 1 diabetes but in a range of other autoimmune and endocrine disorders

This fundamental and clinical field has played a prominent role in advancing the understanding of autoimmunity including creation of the first models of induced autoimmune disease, demonstration that autoimmunity can cause human pathology, and characterization of remarkable syndromes linking multiple autoimmune diseases.

Some of the book’s chapters are highlighted below:

  • Discovering Novel Antigens
  • Characterizing T-Cell Autoimmunity
  • Metabolic Syndrome and Inflammation
  • The Mouse Model of Autoimmune Polyglandular Syndrome Type 1
  • Autoimmune Polyendocrine Syndrome Type I: Man
  • IPEX Syndrome: Clinical Profile, Biological Features, and Current Treatment
  • Autoimmune Polyendocrine Syndrome Type 2: Pathophysiology, Natural History, and Clinical Manifestations
  • Drug-Induced Endocrine Autoimmunity
  • Immunopathogenesis of the NOD Mouse
  • Virus-Induced Type 1 Diabetes in the Rat
  • Autoimmune Pathology of Type 1 Diabetes
  • Natural History of Type 1 Diabetes
  • Immunotherapy of Type-1 Diabetes: Immunoprevention and Immunoreversal
  • Latent Autoimmune Diabetes in Adults
  • Fulminant Type 1 Diabetes Mellitus
  • Insulin Autoimmune Syndrome (Hirata Disease)
  • Lessons from Patients with Anti-Insulin Receptor Autoantibodies
  • Addison’s Disease
  • Animal Models of Autoimmune Thyroid Disease
  • Immunopathogenesis of Thyroiditis
  • Immunopathogenesis of Graves’ Disease
  • Graves’ Ophthalmopathy
  • Hypoparathyroidism
  • Premature Gonadal Insufficiency
  • Celiac Disease and Intestinal Endocrine Autoimmunity
  • Pituitary Autoimmunity

Series: Contemporary Endocrinology; Paperback: 579 pages; Publisher: Humana Press; Softcover reprint of the original 1st ed. 2011 edition (August 23, 2016)

Related stories you may like:
Brain superautoantigens: connections between immune and neural repertoires
Stress and organ specific autoimmunity: a complex interrelationship
Caleb Parry hyperthyroidism and stress
Stress-induced th2 shift and thyroid autoimmunity

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Microglia: gatekeepers for neuropathic pain http://www.brainimmune.com/microglia-gatekeepers-for-neuropathic-pain/ Mon, 17 Sep 2018 16:55:12 +0000 http://www.brainimmune.com/?p=6315 Evolving Concepts Introduction Where acute pain protects an individual from further damage, chronic pain serves no adaptive purpose. Approximately 1 in 5 people suffer from chronic pain, which exacts a substantial toll on the both the individual and on national economies [1–3]. Chronic pain can arise due to unresolved inflammation (e.g., rheumatoid arthritis), damage to […]

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Evolving Concepts

Introduction
Where acute pain protects an individual from further damage, chronic pain serves no adaptive purpose. Approximately 1 in 5 people suffer from chronic pain, which exacts a substantial toll on the both the individual and on national economies [1–3]. Chronic pain can arise due to unresolved inflammation (e.g., rheumatoid arthritis), damage to the nervous system (neuropathic pain), and due to unknown precipitating factors (e.g., fibromyalgia). Specific injuries and diseases that can cause neuropathic pain include traumatic injury (e.g. spinal cord injury), stroke, herpes zoster infection (post-herpetic neuralgia), and multiple sclerosis.

An extensive literature has been devoted to understanding neuropathic pain. Basic science studies have revealed that there are key nervous systems sites for pain modulation. These include the site of injury, the cell bodies of primary afferents (dorsal root ganglia; DRG), the dorsal horn of the spinal cord, and a distributed group of brain regions known as the ‘pain matrix’ [4–7]. Animal studies have predominantly focused on the spinal cord; this site has particular significance for pain, as primary afferent neurons synapse here with pain projection neurons, and are modulated by descending inhibitory neurons and interneurons [5,6]. Therefore, this site will be the focus of this review. Studies in spinal cord have revealed that neuropathic pain is not purely the product of dysfunctional neuronal communication, but that non-neuronal cells, such as microglia, are also critical participants [8,9].

What is the evidence for involvement of microglia in chronic pain?
Microglia are the resident macrophages of the central nervous system (CNS) and play a key role in maintaining homeostasis. Activation of spinal microglia in response to injury of peripheral nerves was first demonstrated in the late 1990s; immunohistochemical and gene expression studies revealed that microglial ‘activation’ markers were rapidly elevated [10,11]. A causal role for microglia in the pain behaviors caused by peripheral nerve injury was then inferred when minocycline treatment was found to prevent pain in rats [12,13]. A key finding of these and subsequent studies (e.g. [14]) was that expression of microglia activation markers peaked within 2 weeks of injury, while inhibition of microglial signaling could prevent, but not reverse, neuropathic pain. This led to the conclusion that microglia participate in the development of neuropathic pain, but not its maintenance. A recent study using Mac1-saporin depletion has claimed that microglia do contribute to the maintenance of neuropathic pain, as their depletion reverses pain behaviors 3 months after nerve injury [15]. However, the consensus view is that microglia are principally early responders to nerve injury.

A limitation to this early research is that pharmacological agents like minocycline also inhibit neurons and astrocytes; the lack of selectivity for microglia confounds interpretation. However, several studies have reinforced evidence for microglial participation in pain. Demonstrating sufficiency for pain, microglia were activated in vitro and then adoptively transferred to naïve male rats, inducing pain behaviors [16]. We have recently expressed Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in spinal microglia, using a cell-selectively promoter [17,18]. Activation of excitatory DREADDs in naïve male rats induced allodynia (sensitivity to innocuous stimuli), supportive of the sufficiency for microglia activation for pain. We also showed that inhibiting microglia with DREADDs could reverse neuropathic pain in males, which demonstrated that microglia are necessary for neuropathic pain.

There is emerging evidence that microglia may contribute to neuropathic pain in a sex-dependent manner. Acute depletion of microglia or inhibition with minocycline reversed neuropathic pain in male rats only [19]. However, these findings are not without controversy [20,21], and additional studies with longer-term treatments are required; when neuropathic pain is fully developed, repeated treatments are often required for reversal. Nonetheless, the accumulating evidence for males-specific engagement of particular signaling pathways will be discussed.

How do microglia become activated after neuronal injury?
Given the evidence that microglia are important cellular mediators of neuropathic pain, investigators next turned to the question of how microglia can respond to nerve injury.
Microglial activation is understood as a change in cell number, morphology, phenotype and motility, the expression of membrane-bound and intracellular signaling proteins, and the release of immunoregulatory products, such as cytokines and chemokines. Microglia express a range of receptors that detect ligands released as a consequence of neuronal injury, and that lead to their activation (illustrated in Fig. 1).

ATP. Injured neurons release ATP in the dorsal horn of the spinal cord [22], which is detected by purinergic receptors expressed by microglia; these include ionotropic P2X4 and P2X7 receptors, and metabotropic P2Y12 and P2Y13 receptors [23,24]. Microglia upregulate surface expression of these receptors after peripheral nerve injury. Their involvement in neuropathic pain has been confirmed in genetic knockout and knockdown studies, as pain behaviors are reduced under these conditions [16,25]. However, the P2X4R pathway is specifically engaged in male rather than female rodents [19,26]. This may be due to differential transcriptional regulation of P2rx4 by the transcription factor IRF5 [26].

Chemokines. Several chemokines are produced and released by injured neurons. At present the strongest evidence supports a role for CSF-1. The cognate receptor CSF-1R is expressed exclusively by microglia in the CNS, and is essential for survival [27]. Peripheral nerve injury induces de novo expression of CSF-1 in the DRG [28]. Conditional knockout of CSF-1 in sensory neurons prevented development of pain behaviors, and reduced microglial activation and proliferation in the spinal dorsal horn [28]. There is evidence that engagement of this pathway may precede activation of microglia via ATP, as the CSF-1R adapter protein DAP12, is upstream of the P2X4R gene.

Other groups have previously suggested that the chemokines CCL2 and CX3CL1 are neuron-glia signals in neuropathic pain [29,30]. However, subsequent studies revealed that microglia express very low levels of CCR2 [31], suggesting a limited role for its ligand CCL2. While microglia uniquely express the receptor for CX3CL1 in the CNS [31], the release of this ligand from neurons is now known to be secondary to microglial activation; CX3CL1 is cleaved by cathepsin S derived from already activated microglia [32]. Furthermore, DAP12 is also upstream of CX3CR1 and cathepsin S genes [28]. Thus, CSF-1 appears to be the principal chemokine to mediate microglial activation after peripheral nerve injury.

Damage associated molecular patterns (DAMPs). According to the danger model of immunogenicity [33], the immune system can respond to cellular damage and the consequent release of DAMPs. Several DAMPs have been implicated in neuropathic pain, including High Mobility Group Box 1 (HMGB1), Heat shock proteins (HSP)-60 and -90, biglycan and fibrinogen [34]. These molecules are typically sequestered within intracellular compartments or the extracellular matrix, and become liberated into the extracellular milieu during stress or damage. It should be noted that the cellular source of many of these DAMPs has not been unequivocally demonstrated. Nonetheless, microglia respond to exogenous administration of DAMPs. Pattern recognition receptors are those capable of detecting such DAMPs, and among this receptor class, Toll-like receptors (TLRs) have been most thoroughly investigated [34].

Of the 13 TLRs expressed in rodents, most research has focused on TLR4. TLR4 is upregulated after peripheral nerve injury. However, evidence for causal involvement in neuropathic pain comes from pharmacological and genetic manipulations: pain behaviors after nerve injury are attenuated when TLR4 or accessory proteins (required for signaling) are inhibited, knocked out, or knocked down [34–36]. There is an emerging role for other TLRs in neuropathic pain, including TLR2, 3, 5, and 9 [34].

Finally, TLR4-dependent pain may be sexually dimorphic. Intrathecal injection of the TLR4 agonist LPS induces allodynia in male (but not female) rats [37]. This is in notable contrast to intrathecal disulfide HMGB1, which induces allodynia in both male and female mice [38]. Reversal of intrathecal LPS-evoked tactile allodynia by the small molecule TLR4 antagonist TAK-242 occurs in male mice, while having no effect on females [39] Similarly, male mice deficient in TLR4 do not develop robust neuropathic pain after peripheral nerve injury, whereas female mice do [40]. This leads to the intriguing possibility of sex differences regarding the involvement of innate immune signaling in the development of neuropathic tactile hypersensitivity. Given the predominance of chronic pain conditions disproportionately afflicting women, it has been argued that interactions between endocrine and immune mechanisms may help explain some of the sex differences observed in the epidemiology of pain disorders [41,42].

Intracellular signaling pathways.Many of the receptors described above converge on common intracellular signaling pathways, including activation of the transcription factor NFB, and p38 and ERK mitogen activated protein kinases (MAPKs). Such activation occurs in spinal microglia after peripheral nerve injury, and leads increased transcription of proinflammatory and pronociceptive cytokines and growth factors [14,43,44]. Other signaling pathways include activation of NADPH oxidase isoform 2 that generate reactive oxygen species [45]. These enzymes and transcription factors are causal to neuropathic pain, as their inhibition or genetic deletion reverses pain behaviors evoked by peripheral nerve injury in male rodents. However, one group has assessed female rodents, and shown that pain behaviors are not reversed when p38 is inhibited [19,46]. This again points to a male-specific role for microglia in neuropathic pain.

How do activated microglia cause pain?
As noted above, a primary consequence of microglial activation is the release of proinflammatory cytokines, growth factors, and reactive oxygen species. These mediators act at central synapses in the spinal cord dorsal horn to disrupt the balance of excitatory and inhibitory neurotransmission (illustrated in Figure 1).

microglia gatekeeprs pain Fig.1

Figure 1. Microglia promote pain sensitization in the dorsal horn of the spinal cord. Injured primary afferent neurons release ATP, chemokines such as CSF-1 and CX3CL1, and danger associated molecular patterns (DAMPs) that activate microglia via surface receptors. Activated microglia release cytokines (IL-1 β, TNF), growth factors (BDNF), and reactive oxygen species (ROS). These signaling mediators act on primary afferent neurons, interneurons, and pain projection neurons to cause neuroexcitation and disinhibition that drives pain sensitization.

Enhanced excitatory synaptic transmission. Cytokines such as TNF and IL-1 increase the excitatory tone of pain projection neurons by enhancing glutamate release and availability [8]. For example, activation of IL-1 receptors that are functionally coupled to presynaptic NMDA receptors promotes glutamate exocytosis [47]. Both IL-1 and TNF can downregulate transporters expressed by astrocytes that are responsible for uptake of glutamate [48,49]; the consequence is excessive glutamate levels in the synaptic cleft. Cytokines and chemokines can also sensitize post-synaptic terminals. The mechanisms include increased trafficking and surface expression of AMPA receptors, and by phosphorylating NMDA receptor subunits [50–53]. Collectively, these studies show that inflammatory mediators released by microglia have the capacity to facilitate hyperexcitability of pain projection neurons.

Reduced inhibitory synaptic transmission. Mediators derived from microglia can also cause disinhibition. Cytokines, chemokines and reactive oxygen species can diminish release of GABA and glycine from interneurons and descending inhibitory projections in the spinal cord [54–56]. Activated microglia also sculpt synaptic elements in the spinal dorsal horn and excessively prune GABAergic terminals [57]. The growth factor BDNF activates TrkB receptors on postsynaptic terminals, reducing expression of the KCC2 potassium-chloride cotransporter [58]. This leads to increased intracellular Cl- concentrations that weaken GABA receptor mediated hyperpolarization. Only males exhibit BDNF-dependent neuropathic pain [19]; this result is consistent with BDNF release requiring P2X4 receptor and p38 MAPK activation, which themselves are activated in a sexually dimorphic manner [26,46]. The consequence of these disinhibitory mechanisms is to increase the excitability of pain projection neurons.

Future directions and conclusions
A major challenge for the future is to translate the findings from animal models into humans. Imaging studies are yielding very promising results using radioligand binding to TSPO, a putative marker of glial activation. Binding was increased in thalamic nuclei, somatosensory cortices of patients with low back pain [59], and the neuroforamina and spinal cords of patients with lumbar radiculopathy [60]. Further work is required to understand the function of TSPO in neuropathic pain and to develop new radioligands. Firstly, it is unclear whether TSPO expression correlates with activation [61]. Secondly, there is some evidence that TSPO has anti-inflammatory function [62], and thus only a subset of glia may be labelled. Which subset that may be, and its relationship to neuropathic pain, need to be defined. Finally, the selectivity of TSPO to microglia is a matter of debate that needs clarification [63]. Nonetheless, these studies provide compelling evidence for the association of glial activation in human chronic pain states. PET imaging may also be a useful tool to validate target engagement for development of novel therapeutics that target microglia.

The vast majority of studies have focused on microglia in the spinal cord. However, the sensory and affective components of chronic pain are ultimately encoded in the brain, as noted above. Several groups, including my own, are now beginning to investigate how microglia in the brain contribute to the multi-dimensional experience of chronic pain [64,65].

The evidence summarized here highlights a critical role for microglia in the initiation of neuropathic pain, especially in male rodents. Given that women predominantly suffer with chronic pain, studies should now be directed towards identifying whether microglia are truly a relevant clinical target for treatment of chronic pain; dysfunctional synaptic plasticity induced by activated microglia is a promising therapeutic avenue for a disease that is poorly managed and causes untold suffering.

Author Affiliations:

Peter M. Grace, PhD – Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030; e: pgrace@mdanderson.org

List of Non-Standard Abbreviations

CNS, central nervous system; DRG, dorsal root ganglia; DREADDs, designer receptor exclusively activated by a designer drug; DAMP, damage associated molecular pattern; IL-1, interleukin-1; TLR, toll-like receptor; TNF, tumor necrosis factor.

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Lessons Learned from the Hibernating Brown Bears http://www.brainimmune.com/lessons-learned-from-the-hibernating-brown-bears/ Sat, 15 Sep 2018 14:05:56 +0000 http://www.brainimmune.com/?p=6296 “The Mind-Gut Connection“, written by Emeran Mayer, M.D., demonstrates his vast experience as a practicing gastroenterologist as he describes the connections that our brains have with our guts, especially with the microbes that make the gut their home. Mayer is a world renowned gastroenterologist and neuroscientist with 35 years of experience in the study of clinical […]

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The Mind-Gut Connection, written by Emeran Mayer, M.D., demonstrates his vast experience as a practicing gastroenterologist as he describes the connections that our brains have with our guts, especially with the microbes that make the gut their home.

Mayer is a world renowned gastroenterologist and neuroscientist with 35 years of experience in the study of clinical and neurobiological aspects of how the digestive system and the nervous system interact in health and disease. His current research focus is on the role of the gut microbiota brain interactions in emotion regulation, chronic visceral pain and in obesity.

Obesity and compromised metabolic health are often thought to be closely linked. However, a study by Fredrik Baeckhed’s group at the University of Gothenburg suggests that this is not necessarily the case – at least in brown bears!

By studying body weight and the gut microbiota in brown bears both during the summer and during the winter period – when these animals go into a 6 months hibernation period – they identified major differences in the diversity and relative abundances of certain gut microbiota. During the summer the bears overeat and dramatically gain body weight, while during the prolonged fasting period in winter they lose all the excess weight. The most fascinating aspect of this study was that despite their “summer obesity” the bears did not develop the negative metabolic changes including insulin resistance and diabetes known as metabolic syndrome, a metabolic dysregulation which has shown a dramatic increase in North America and other developed countries.

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Dr. Mayer is currently Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA, Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience, and Co-director of the CURE: Digestive Diseases Research Center at UCLA.

The post Lessons Learned from the Hibernating Brown Bears appeared first on BrainImmune: Trends in Neuroendocrine Immunology.

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