Microglia in Fibromyalgia Overproducing TNF-α
The 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.
In 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
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