Shared Fate of Meningeal Mast Cells and Sensory Neurons in Migraine

Abstract

Migraine is a primary headache disorder which has complex neurogenic pathophysiological mechanisms still requiring full elucidation. The sensory nerves and meningeal mast cell couplings in the migraine target tissue are very effective interfaces between the central nervous system and the immune system. These couplings fall into three categories: intimacy, cross-talk and a shared fate. Acting as the immediate call-center of the neuroimmune system, mast cells play fundamental roles in migraine pathophysiology. Considerable evidence shows that neuroinflammation in the meninges is the key element resulting in the sensitization of trigeminal nociceptors. The successive events such as neuropeptide release, vasodilation, plasma protein extravasation, and mast cell degranulation that form the basic characteristics of the inflammation are believed to occur in this persistent pain state. In this regard, mast cells and sensory neurons represent both the target and source of the neuropeptides that play autocrine, paracrine, and neuro-endocrine roles during this inflammatory process. This review intends to contribute to a better understanding of the meningeal mast cell and sensory neuron bi-directional interactions from molecular, cellular, functional points of view. Considering the fact that mast cells play a sine qua non role in expanding the opportunities for targeted new migraine therapies, it is of crucial importance to explore these multi-faceted interactions.

Mast Cells in Gut and Brain and Their Potential Role as an Emerging Therapeutic Target for Neural Diseases

“…They migrate to locate in mucosal and connective tissues completing their differentiation in mature MCs on the influence of local residing microenvironment, which defines their phenotype and, consequently, their function (Beaven, 2009; De Zuani et al, 2018). In particular, MCs represent about 2–3% of the immune cellular pool of the lamina propria, and in the muscular and serous layers (3,000–25,000 MCs/mm 3 ), located in strategic position in proximity of blood, lymphatic vessels, and nerves (Irmak et al, 2019). Stem cell factor (SCF) binds to c-kit tyrosine kinase receptor of MCs and it is a necessary component for their survival, proliferation, and differentiation (Okayama and Kawakami, 2006).…”

“…CNS is involved not only in spino–thalamic–cortical pain system, but also in the limbic areas, which modulate the component emotional-affective of pain, as well as in the cognitive areas, which modulate adaptive, motivational, and relational aspects (Mannion and Woolf, 2000). Headache is one of the main symptoms associated with these conditions (Irmak et al, 2019). Evidence shows the involvement of MCs on pain and stress (Eller-Smith et al, 2018).…”

“…MCs and nerves communicate bi-directionally. Calcitonin gene-related peptide (CGRP) released from meningeal nociceptors may degranulate MCs that release histamine that, in turn, activates mechanosensitive C-fibers that release CGRP and substance P (SP) (Julius and Basbaum, 2001; Irmak et al, 2019). Actually, CGRP co-localizes with SP and both neurotransmitters were found adjacent to mucosal MCs.…”

“…Afferent fibers express the receptors involved in nociception, such as transient receptor potential vanilloid 1 (TRPV1), transient receptor potential ankyrin 1 (TRPA1), and proteinase-activated receptor 2 (PAR2) (Kim et al, 2010). The activation of PAR2 starts downstream sensitization of TRPV1 and TRPA1 involved for the generation of visceral hyper-sensibility (Amadesi et al, 2006; Irmak et al, 2019). PAR-2 is expressed by dorsal root ganglia that co-express TRPV1, TRPV4, TRPA1, and SP and CGRP, is activated by tryptase and SP, and its activation can result in neurogenic inflammation (Amadesi et al, 2006).…”

“…Evidences suggest that MCs may upgrade a cascade of inflammatory events that result in trigeminal activation (Levy et al, 2006; Irmak et al, 2019). MC releases nitric oxide (NO), crucial mediator of persistent neuronal damage triggering neurogenic inflammation (Ramachandran et al, 2014; Ramachandran, 2018).…”