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:
- CGRP antagonist: BIBN 4096BS
- TRPV1 agonist: Capsaicin
- NGF antagonist: K252a
- Inhibitor of the protein tyrosine kinase Syk: GSK 143
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.