Mast Cells, Neuroinflammation and Pain in Fibromyalgia Syndrome

1Fibromyalgia Syndrome is a disorder of chronic generalized muscular pain, stiffness, generalized fatigue, sleep abnormalities, and cognitive problems assessed by the FSQ, which has about 93% sensitivity and 92% specificity. FMS affects about 5% of adults, primarily women 20–60 years of age and belongs to a family of overlapping painful conditions (Table 1) known as CSS. Central sensitization is recognized as the main mechanism involved and is characterized by allodynia, pain from an otherwise non-painful stimulus, and hyperalgesia due to an exaggerated response to a painful stimulus. The pathogenesis of FMS remains unknown and with no objective diagnostic criteria. FMS patients have reduced tolerance to pain, especially extremes of heat and cold. There is considerable evidence of altered circuity of pain networks and abnormal pain processing in FMS.

2The PubMed database was searched between 1960 and 2018 using the terms fatigue, fibromyalgia, hypothalamus, inflammation, mast cells, pain and stress. Only articles in English were included.

3Here we discuss how brain mast cell release of neuro-sensitizing mediators in the thalamus leads to focal inflammation and contribute to the pathogenesis of FMS.

4It was recently proposed that FMS may involve localized inflammation in the hypothalamus. Elevations in pro-inflammatory chemokines/cytokines could negatively impact symptoms leading to sensitization of peripheral and central nociceptors. Increased levels of the pro-inflammatory chemokine IL-8 (CXCL8) have been reported in the serum and CSF in patients with FMS. Chemokines facilitate nociception by directly acting on chemokine receptors present along the pain pathway.

5The cytokines TNF and IL-17 greatly contribute to the inflammatory response. Plasma levels of IL-17 were increased and correlated with levels of TNF in patients with FMS. CSF and serum IL-17 also positively correlated with pain and anxiety. Mast cells, themselves, can secrete IL-17; moreover, IL-6 and TGFβ from mast cells contribute to the development of Th-17 cells.

6Fibromyalgia syndrome worsen by stress, which augments pain responses. Plasma concentrations of cortisol are increased in the evening, suggesting disruption of the circadian rhythm. Serum levels of CRH, which is secreted under stress, were increased in patients with FMS. CRH was also increased in the CSF of such patients and correlated with severity of pain. Physiological stress was reported to be the most common trigger in patients with systemic mastocytosis (SM) who also commonly experience FMS. We reported increased levels of CRH in the serum of one patient with indolent systemic mastocytosis. CRH can trigger human mast cells to release VEGF without histamine or tryptase. CRH also has synergistic action with NT stimulating VEGF release. As a result, there is increased vascular permeability in the skin and the blood-brain barrier (BBB). Stress also disrupts the gut-blood barrier allowing for gut microbiome-associated molecules, such as propionate to enter the brain and contribute to focal inflammation. These results have led to the conclusion that mast cells may serve as “immune gate to the brain”.

7Levels of the neuropeptide SP and NGF are elevated in the CSF of FMS patients. NGF has been reported to increase nociception and hyperalgesia. The SP receptor NK-1 has been involved in the pathophysiology of pain. We reported increased serum levels of SP, its structural analogue Hemokinin-1 (HK-1) and TNF in patients with FMS. SP and NGF can stimulate mast cells. Moreover, SP induced mast cell expression of CRHR-1. Cerebrovascular mast cells were stimulated by CGRP, which is now well established to participate in the pathophysiology of headaches. In addition to neuropeptides, sex hormones can also affect mast cell reactivity. For instance, estradiol augments immune and allergic processes. In particular, we had reported expression of estrogen receptors on rodent mast cells. We also reported that 17β-estradiol further increased stimulation of mast cells by SP. Such findings may help explain why FMS is more common in women.

8In addition to allergic reactions, mast cells contribute to innate immunity, autoimmunity and inflammation.

9Increasing evidence supports the involvement of mast cells in FMS and comorbid disorders as well as other inflammatory and painful conditions, as well as neuroimmune interactions (Figure 1). Chronic urticaria, which involves stimulation of skin mast cells is more common in FMS. Moreover, mast cells are significantly increased in the papillary dermis of FMS patients. The chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2) and eotaxin (CCL-11) are elevated in plasma of FMS patients. MCP-1 is a strong mast cell chemoattractant and also triggers mast cells in rodents. MCP-1 induced prolonged muscle hyperalgesia in rats via activation of its high-affinity receptor, CC Chemokine receptor 2 (CCR2), on the peripheral nerve terminals. Myoblasts treated with MCP-1 secreted significant amounts of the key pro-inflammatory cytokine IL-1β. C-reactive protein (CRP) is now considered a marker of chronic inflammation. CRP may be useful in the diagnostic of FMS (and depression/anxiety that often accompany FMS), even though there is no direct correlation reported.

10Mast cells derive from the bone marrow and mature in response to SCF, which acts via the cell surface tyrosine kinase KIT receptor. Mast cell progenitors then migrate in all tissues. As a result, mast cell mediators can affect all organs and lead to multiple symptoms. Mast cells are found adjacent to blood vessels and nerve endings; in the brain, mast cells are located in the thalamus, hypothalamus and median eminence.

11Mast cells are known to be stimulated by IgE, via activation of its unique surface receptors (FcεRI). Mast cells can also be stimulated via TLRs,. Stimulated mast cells secrete multiple vasoactive, pro-inflammatory and neuro-sensitizing molecules. Stimulation of mast cells can be augmented by the cytokine IL-33, which synergizes with SP to induce release of impressive amounts of VEGF, TNF or IL-1β. As a result, mast cells can serve as “sensors of cell danger”.

12Mast cell secretory granules store many preformed pro-inflammatory and neuro-sensitizing mediators including bradykinin, histamine, TNF and tryptase. Mast cells also release de novo synthesized molecules: (a) lipid mediators (leukotrienes, prostaglandins, and PAF), (b) cytokines (IL-6, IL-13, IL-33, TNF) and (c) chemokines (CXCL8, CCL2, CCL5),. Mast cell could often release mediators selectively without histamine or tryptase. Mast cells also release IL-31, which is important in the sensation of itching and pain, in response to IgE and SP, IL-33 and specifically their combination. We reported that mast cells can release mtDNA, which is mistaken as a pathogen and stimulates inflammatory responses.

13Finally, mast cells can release extracellular vesicles (exosomes) that could deliver regulatory molecules, including mtDNA and microRNAs. Such microvesicles have been implicated in brain disorders and pain disorders. We recently reported that extracellular vesicles are increased in the serum of children with ASD, contained mtDNA and stimulated cultured human microglia to secrete the pro-inflammatory molecules IL-1β and CXCL8.

14Mast cells communicate with microglia. Mediators secreted from mast cells, such as histamine and tryptase, can activate microglia leading to secretion of the pro-inflammatory cytokines IL-1β, IL-6 and TNF. Microglia can also be activated by CRH secreted from mast cells. Stimulation of brain mast cells in mice led to activation of microglia, which was decreased by administration of a mast cell inhibitor.

15Microglia are involved in synapse plasticity, but are responsible for innate immunity of the brain. Microglia contribute to brain inflammation and the pathogenesis of different brain disorders, especially ASD. Microglia in the thalamus have been discussed in the context of pain, especially maintaining the pain sensation even after the original painful stimulus is not present.

16Mast cells have been implicated in headaches and pain. Activation of the mast cell-specific receptor, MRGPRX2, and its mouse analogue, Mrgprb2, mediated inflammatory mechanical and thermal hyperalgesia. Hence, mast cells are key players of neuroendocrine and painful disorders.

17In this context, inhibitors of mast cells would be useful in the treatment of FMS. Natural molecules could include the flavonoids, luteolin and tetramethoxyluteolin, alone or in combination with other substances selected to reduce stress. Other natural molecules could include palmitoylethanolamide, which apparently inhibits neuro-inflammation and reduces pain.

18Research should focus on identifying in serum of patients with FMS novel molecules that are involved in pain transmission such as bradykinin, CGRP and IL-31. Extracellular vesicles should also be isolated from the serum and CSF of FMS patients, their content identified, and their effect investigated on cultured human mast cells and microglia. Such possible interactions would serve as useful in vitro assays for the screening of potential novel treatment agents. Recent reports have also stressed the possible use of the cytokine IL-37, which is known to have anti-inflammatory actions. It would be important to explore the possible use of IL-37 isoforms in the treatment of FMS.

19TT, IT, and MB participated in searching the literature. TT and IT wrote or contributed to the writing of the manuscript. IT prepared the figure.

20TT is the inventor of US patents No. 7,906,153 and No. 8,268,365 for the treatment of neuroinflammatory conditions. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.