Figure 2:
Schematic illustration of mast cell-nerve interactions, mast cell and intestinal barrier function elements interactions in gut and pharmacological targets. The classical stimulus for mast cells activation is the binding of immunoglobulins E (IgE) on its high-affinity receptor FcεRI cell surface prior to cross-linking by allergen in a sensitised individual. This leads to a cascade of phosphorylation, transcription of pro-inflammatory factors, and to cytokine production and to histamine degranulation notably. The protein tyrosine kinase Syk participates to this process through autophosphorylation and activation of intracellular signaling.In-vitro studies showed that GSK 143 (syk inhibitor) blocked substance P activation and decreased cytokine expression. MCs and nerve endings communicate bidirectionally and thus modulate peristalsis and visceral pain. The secretion of bioactive pro-inflammatory mediators by the MCs (such as histamin, leucotriens and proteases) results in numerous effects on neurons such as activation, sensitisation and recruitment of nociceptors to the cell membrane, neurogenic inflammation, thus increasing sensitivity and visceral pain. In the other direction the activation of neurons leads to the release of neuropeptides and neurotransmitters that activate the MCs. MCs are activated by NGF via the high-affinity NGF receptor, tropomyosin receptor kinase A. Its antagonist K252a prevented degranulation of mast cells and decreased the expression of inflammatory markers such as IL6. The interaction between the afferent neuron and the MCs can take place between the secretion of CGRP and substance P and their interaction on the MCs via RAMP-1, CALCRL (CGRP) and NK-1 receptors (substance P). The MCs interact with the intestinal barrier function, particularly at the level of the TJs via the activation of PAR-2 receptors.
Pharmacological targets:
Abbreviations:
TJ, tight junction; CRGP, calcitonin-related gene peptide; H1R, histamine receptor 1; IgE, immunoglobulins E; NK1, neurokinin 1 receptor; NGF, neuronal growth factor; PAR2, proteinase-activated receptor-2; TRPV1, transient receptor potential vanilloid 1; TRPA1, transient receptor potential ankyrin 1; TrkA, receptor for nerve growth factor, PAR2, proteinase-activated receptor-2, RAMP1, receptor activity modifying protein 1; CALCRL, Calcitonin receptor-like; FcεRI, high affinity IgE receptor.