Chemokines CX3CL1 IL-8 – Fibromyalgia
A new study published in the Journal of Pain Research reports the presence of high levels of the chemokines CX3CL1 (also known as fractalkine) and interleukin-8 (IL-8) in fibromyalgia (FM) patients.
Fibromyalgia is the “current term for chronic widespread musculoskeletal pain for which no alternative cause can be identified”. Typical symptoms includes chronic widespread pain, paresthesias, allodynia, fatigue, sleep difficulties and cognitive impairment. The prevalence of FM is ~2% worldwide, and it is more common in women.
There is a need to better understand the pathophysiological mechanisms of FM, and such knowledge would perhaps enable the development of better therapeutic drugs. Central sensitization, defined as nociception-driven amplification of neural signaling within the central nervous system leading to pain hypersensitivity, is considered to be an important pathophysiological mechanism in chronic pain conditions, not least in FM.
It appears that both neuroendocrine and immune dysfunctions contribute to the pathophysiology of FM. This includes sympathetic dysautonomia characterized by relentless sympathetic hyperactivity accompanied by sympathetic nervous system hypo-reactivity to different stressors. The inflammatory/immune component is characterized by the involvement of cytokines and chemokines such as IL-8 and IL-17.
Thus, plasma and/or serum levels of proinflammatory cytokines IL-6 and IL-8 are elevated in patients with FM, as were cerebrospinal fluid (CSF) levels of IL-8 in one study. Indeed, the CSF is a relevant body fluid to investigate in pain conditions, as it is in direct contact with the CNS and can be hypothesized to mirror CNS pathology. CSF levels of classical neuropeptides such as substance P, beta-endorphin and other endogenous opioids have therefore been studied in many different pain states.
In the Journal of Pain Research study, Emmanuel Bäckryd and colleagues from the Pain and Rehabilitation Center, Linköping University, Sweden investigated the CSF and plasma inflammatory profiles of FM patients compared with healthy controls.
Instead of analyzing only a few substances at a time, the investigators applied the multiplex proximity extension assay (PEA) in which 92 proteins were simultaneously analyzed in cerebrospinal fluid (CSF) and plasma samples from 40 FM patients. They determined the CSF and plasma inflammatory profiles of 40 FM patients compared to healthy controls (CSF) and blood donors (plasma).
The authors found elevated IL-8 levels in both CSF and plasma FM samples, confirming previous reports, whereas high levels of CX3CL1 were monitored only in CSF samples. As per the authors, this may indicate the presence of both neuroinflammation and chronic systemic inflammation in FM.
Regarding the question of causality, the authors discuss and hypothesize 3 major scenarios: 1) their results reflect the involvement of these chemokines in the pathophysiology of FM; 2) they reflect a risk factor present prior to the development of chronic pain, and 3) they may indicate just a consequence of the chronic pain condition, and “mirroring pain-related stress, inactivity, depression or bad sleep”.
As per the authors, one could for instance hypothesize that some individuals are more inflammation prone at the outset (a risk factor) and that they therefore develop a strong neuroimmune and/or systemic reaction leading both to the experience of pain and to other symptoms of the “sickness syndrome”.
Disentangling the contribution of these potentially mutually interacting factors will be very difficult. For instance, levels of peripheral IL-6 are known to be influenced by regular exercise, individuals who are inactive having higher baseline levels of this particular cytokine.
It is known that the CX3CL1/ fractalkine is “found commonly throughout the brain, particularly in neural cells, and its receptor is known to be present on microglial cells”, whereas “IL-8 is the first endogenous mediator to be identified as evoking hyperalgesia involving the sympathetic nervous system”.
Of note, Kathleen Sluka and Daniel Clauw recently stated that “fibromyalgia and related disorders are heterogenous conditions, with patients falling along a continuum with one end a purely peripherally driven painful condition and the other end of the continuum is when pain is purely centrally driven”.
Thus, it is interesting whether future studies may identify a stratification of FM patients in terms of CX3CL1 and IL-8 levels.
Source: J Pain Res, 2017; 10: 515–525.
Read more: Journal of Pain Research
Updates
2022
A 2022 meta-analysis (data from 40 studies) by Dinesh Kumbhare et al., published in Pain showed that patients with FM had significantly lower levels of interleukin-1 β and
higher levels of IL-6, IL-8, tumor necrosis factor-alpha, interferon gamma, C-reactive protein, and brain-derived neurotrophic factor
compared with healthy controls.
Nevertheless, this systematic literature review and meta-analysis
could not support the notion that these blood biomarkers are specific biomarkers of FM.
2023
A 2023 systematic review by Isabel Hong-Baik et al. found evidence of elevated cytokine levels in patients with FM, suggesting low chronic inflammation and a possible contribution to central sensitization and chronic pain.
The studies and results, discussed in this review, also provided a possible explanation for many of the symptoms experienced by FM patients. For example,
elevated concentrations of IL-6 and IL-8 have been shown to have additive or synergistic effects on the perpetuation of chronic pain in these patients.
IL-6 induces pain, fatigue, and psychiatric disorders such as depression and stress, while IL-8 is associated with pain and sleep disorders. Consequently, an imbalance between proinflammatory and anti-inflammatory cytokines contributes to chronic peripheral sensitization of the nervous system and pain processing.
Another 2023 study by Eduardo Otero et al., published in Biomedicines, determined possible differences in the performance of physical activity and psycho-neuro-immunoendocrine biomarkers in women with FM, with and without a previous chronic fatigue syndrome (CFS) diagnosis.
Background: Previous research indicates that dysregulation of the bidirectional interaction of the cytokine- hypothalamic-pituitary-adrenal (HPA) axis can aggravate inflammatory conditions, due to a reduced response of the HPA axis to cytokines or to the development of glucocorticoid resistance. Thus, disruption of this feedback in FM is associated with a severely dysregulated interaction between the immune/inflammatory and stress responses, particularly mediated by systemic IL-8 and cortisol.
Figure 1. Serum levels of IL-8 in FM patients with (FM + CFS) or without (FM) CFS diagnosis. From: Eduardo Otero et al., Biomedicines, 2023 May 20;11(5):1488. doi: 10.3390/biomedicines11051488.
In this context, as per the authors, previous research also indicates that the HPA axis failed to control the increase in pro-inflammatory cytokines.
Interestingly, the results obtained in the 2023 study by Eduardo Otero et al., showed this dysregulation in the interaction between the IL-8-mediated inflammatory response and the cortisol-mediated stress response
only in patients without a previous CFS diagnosis.
Of note, FM patients with a previous CFS diagnosis had lower systemic levels of IL-8, cortisol, oxytocin, and higher levels of adrenaline and serotonin than FM patients without diagnosed CFS.
Thus, according to the authors, their results would
suggest that patients with a CFS diagnosis may be over-diagnosed with FM
through subjective questionnaires and without the analysis of objective biomarkers, since all previous investigations of their research group showed that women with FM showed elevated levels of IL-8 in relation to healthy women.
In conclusion, the authors suggested that their results indicated that while perceived health related to fatigue and physical activity capacity, psychological disorders and pain are not affected by a previous CFS diagnosis; physical activity and sedentary lifestyle parameters and objective neuro-immuno-endocrine biomarkers related to stress, depression and pain were only manifested in patients without a CFS diagnosis. This suggests a possible overdiagnosis of FM in CFS patients when it is assessed only through perceived symptoms and not with objective immune-physiological parameters.
2024
A 2024 study by María Elena González-Álvarez et al., published in Cells, showed that
IL-6 and IL-8 may particularly serve as biomarkers for pain severity and disability in FM patients,
showing significant associations with worse clinical outcomes. Elevated IL-8 levels, for instance, correlated strongly with increased pain perception and higher disability scores.
The authors reported that
elevated IL-6 levels were associated with higher Fibromyalgia Impact Questionnaire (FIQ) scores,
indicating worse disability. The authors also reported that participants with
higher IL-8 levels tended to report greater pain intensity and more severe functional impairment.
Thus, according to the authors their findings suggest that systemic neuroinflammation, as reflected by elevated interleukins levels, is closely associated with worse clinical outcomes in FM patients, supporting the hypothesis of a link between neuroinflammatory processes and symptom severity in this condition.
The authors concluded that their observations highlighted the importance of IL-6 and IL-8 as potential biomarkers and mediators of pain severity and disability in FM patients. As per the authors further investigation is warranted to elucidate the mechanistic pathways linking cytokines, systemic inflammation and pain modulation, to potentially guide targeted therapeutic strategies for managing this complex syndrome.
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