Microglia in Fibromyalgia is Hypersensitive and Overproducing TNF-α

Microglia Fibromyalgia Overproducing TNF
Microglia in Fibromyalgia

Update at BrainImmuneThe first study suggesting abnormal activation of microglia in fibromyalgia, published in Scientific Reports, indicates that microglia in patients with fibromyalgia are probably hypersensitive and overproducing tumor necrosis factor (TNF)-α in response to the neurotransmitter ATP.

Fibromyalgia, a representative form of non-organic pain, is a chronic disease that causes severe systemic pain with psychological suffering, resulting in disability and a lowered quality of life.

Microglia are immune cells in the CNS, and known to have inflammatory functions via releasing proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β.

Both dysautonomia and cytokine abnormalities have been implicated in the pathogenesis of fibromyalgia. fMRI studies in humans suggests a hyper-responsiveness characterized by cortical or subcortical augmentation of pain processing in fibromyalgia patients, whereas rodent studies implicate a hyperactive microglia contributing to the pathophysiology of chronic pain.  Thus, as clinical data in humans are not available due to ethical and technical issues, techniques that develop human microglia-like cells from non-brain tissues have been warranted.

Microglia Fibromyalgia Overproducing TNFIn the Scientific Reports study, Masahiro Ohgidani et al. used a novel technique to induce microglia-like (iMG) cells directly from human peripheral blood (monocytes) by applying cytokine IL-34 and granulocyte macrophage colony-stimulating factor (GM-CSF). The authors obtained and developed iMG cells from 14 patients with fibromyalgia and 10 healthy individuals, and compared the activation of iMG cells in these two groups upon stimulation with ATP.

Of note, extracellular ATP is known to operate as a neurotransmitter and/or neuromodulator in the central and peripheral nervous systems. Moreover, ATP functions as a neuromediator at the brain-immune interface and modulates various physiological functions of microglia. Also, previous animal models and research link ATP with chronic pain and chronic pain mechanisms.

Ohgidani et al. found that the TNF-α mRNA expression and TNF-α protein levels were significantly higher in ATP-stimulated iMG cells from patients with fibromyalgia. Of note, PBMC-derived macrophages also expressed an enhanced TNF-α expression upon ATP stimulation, suggesting that the enhanced TNF-α expression in fibromyalgia patients is most likely not specific to iMG cells.

Interestingly, the authors also observed moderate correlation between ATP-induced up regulation of TNF-α expression and clinical parameters of subjective pain intensity assessed by the visual analog scale (VAS). As fibromyalgia is a disease that is often comorbid with conditions such as depression and anxiety, it is interesting to note the authors also found a moderate positive correlation between TNF-α expression level and the severity of both anxiety and depression.

Thus, the study of Ohgidani et al. suggests an abnormal activation of microglial cells and a TNF-hyperresponsiveness to extracellular ATP in fibromyalgia.

This study may also indicate a positive relationship between microglial abnormality and clinical symptoms of fibromyalgia. The microglia-derived TNF-α may represent a possible pathogenic factor in fibromyalgia.

This is substantiated by previous research implicating TNF-α in neuropathic pain and suggesting that  the pathologic level of brain TNF is a therapeutic target for chronic pain treatment.

The study of Ohgidani et al. may also shed new light on clarifying dynamic molecular pathologies of microglia and on developing objective assessment tools in a variety of non-organic brain diseases.

Source: Sci Rep, 2017; 7(1):11882. doi: 10.1038/s41598-017-11506-4.
Read more: Scientific Reports


A 2023 review by Ahd Atta et al., published in Inflammopharmacology discusses the main pathophysiological mechanism for developing nociplastic pain, including fibromyalgia as the prototypical nociplastic pain disorder. Short highlights from this excellent work are provided below.

Nociplastic pain

Nociplastic pain develops due to changes in nociceptive processing, probably due to central sensitization (CS), which causes amplification of neural signaling and alteration in pain modulation, ultimately elicits pain hypersensitivity. Nociplastic pain disorders are often coupled with other comorbidities, such as sleep disturbances, fatigue, memory dysfunction, and mood problems.

Examples for nociplastic pain are fibromyalgia and irritable bowel syndrome. Central sensitization can explain why many people suffer from chronic non-specific pain in the total lack of nerve or tissue damage and a clear activator of nociceptors. The International Association for the Study of Pain (IASP) was among the first to recognize the CS phenomenon, introducing the term “nociplastic pain” in 2017 as the third type of pain, which is distinct from nociceptive and neuropathic pain.

Microglia, M1 and M2 microglia

The microglia polarization towards M1 phenotype represents the classical activation pathway. M1 microglia are the primary responders to an insult. Bacterial-derived products like lipopolysaccharide (LPS), cytokines released by TH1 cells and astrocytes like interferon-γ and tumor necrosis factor-α (TNF-α), and trauma-induced cellular debris all activate the M1 phenotype.

M2 microglia

The microglia polarization towards M2 phenotype characterises the alternative activation pathway. Switching the activation phenotype towards M2 might have a silencing impact, resulting in reintroducing environmental homeostasis and inducing recovery as opposed to the M1 classical activation pathway. The existence of IL-4, IL-10 or IL-13 induces M2 activation.

M1/M2 imbalance and microgliosis as a primary hallmark of neuroinflammation and a driver of nociplastic pain

Patients with nociplatsic pain disorders e.g. fibromyalgia show imbalance in normal M1/M2 pattern. In fibromyalgia, serum levels of M1 macrophage markers along with proinflammatory cytokines and chemokines are enhanced, contributing to systemic inflammation. Instead, levels of M2 microglia markers and anti-inflammatory cytokines and chemokines are decreased, resulting in unopposed chronic central inflammatory state.

FM M2 microgliaIllustration and Graphical Abstract. Illustrating the mechanisms underlying microglia activation in central sensitization and nociplastic pain. LPS lipopolysaccharide, TNF-α tumor necrosis factor-α, INF-γ Interferon gamma, ATP adenosine triphosphate, etc. For the full list of abbreviations used in this figure, see the Inflammopharmacology publication. From: Microglia polarization in nociplastic pain: mechanisms and perspectives, by Ahd Atta et al. Inflammopharmacology, 2023 Jun;31:1053.

At the level of spinal cord, microglia activation is modulated by several neuromolecules including adenosine triphosphate (ATP), chemokine CC motif ligand 2 (CCL2), chemokine CX3C motif ligand 1 (CX3CL1, known as fractalkine), colony-stimulating factor 1 (CSF-1), and SP. ATP induces microglia activation through stimulation of the purinergic P2Y receptors (P2Y12, P2Y13) and P2X receptors.

Targeting microglia as a new therapeutic strategy in treating nociplastic pain

As increased microglial activity contributes to neuroinflammation and CS in patients having chronic nociplastic pain, targeting microglia cells may represent a reasonable new therapeutic approach. Thus, microglial modulators on M1/M2 microglial polarization may offer a novel therapeutic alternative for the management of nociplastic pain disorders.

In conclusion, it appears that the microglia activation and polarization into the M1 phenotype and the subsequent release of proinflammatory chemokines and cytokines are essential for developing neuroinflammation which results in pain hypersensitivity and development of chronic nociplastic pain. Therefore, microglial modulators may have therapeutic potential through suppressing microglia-mediated neuroinflammation.

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