The Chemokines CX3CL1 and IL-8 May Be Implicated in the Pathogenesis of Fibromyalgia

chemokines fibromyalgia
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

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