Figure 2.

Neuron-mast cell crosstalk in the intestine.

((a) and (b)) Neuronal stimulation of mast cells via the neuropeptides vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and substance P (SP) cause mast cell degranulation driving neurogenic inflammation. In the context of psychological stress, SP is also released by nervous terminals, specifically acting on eosinophils. In turn, these immune cells produce corticotrophin releasing hormone (CRH) triggering mast cell degranulation via the CRF1 receptor. ((a) and (c)) Mast cell activation in response to IgE crosslinking or stress triggers the release of mast cell mediators including histamine, serotonin (5-HT), prostaglandins and pro-inflammatory cytokines. In particular, histamine and mast cell tryptase activate afferent neurons through their interaction with the histamine receptor 1 (H1R) and protease-activated receptor 2 (PAR2), respectively. This leads to the activation and sensitization of nociceptors by potentiating transient receptor potential (TRP) vanilloid 1 (TRPV1), TRPV4 and TRP ankyrin (TRPA)1 leading to an aberrant pain response. Also 5-HT increases afferent neuron discharge and sensitizes TRPV1 and TRPV4 channels. Other abbreviations: RAMP1, receptor activity modifying protein 1; CALCRL, Calcitonin receptor-like; NK1, Neurokinin 1 receptor, VCAP, vasoactive intestinal peptide; 5,6-epoxyeicosatrienoic acid (5,6-EET).