CGRP, a neurotransmitter of enteric sensory neurons, contributes to the development of food allergy due to the augmentation of microtubule reorganization in mucosal mast cells

Abstract

Neuro-immune interaction in the gut is substantially involved in the maintenance of intestinal immune homeostasis and the pathology of intestinal immune diseases. We have previously demonstrated that mucosal mast cells and nerve fibers containing CGRP, a neurotransmitter of intrinsic enteric sensory neurons, are markedly increased and exist in close proximity to each other in the colon of food allergy (FA) mice. In the present study, a CGRP-receptor antagonist BIBN4096BS significantly alleviated allergic symptoms in the murine FA model. In addition, the elevated numbers of mucosal mast cells in the proximal colon of FA mice were significantly decreased in that of BIBN4096BS-treated FA mice. Thus, we investigated the effects of CGRP on calcium-independent process in degranulation of mucosal mast cells since CGRP increases intracellular cAMP levels, but not Ca 2+ concentration. CGRP did not alter a calcium ionophore A23187-increased cytosolic Ca 2+ concentration in mucosal-type bone marrow-derived mast cells (mBMMCs), but did augment microtubule reorganization in resting and A23187-activated mBMMCs. Furthermore, CGRP alone failed to cause the degranulation of mBMMCs, but CGRP significantly enhanced the degranulation of mBMMCs induced by A23187. Together, these data indicate that CGRPenhanced microtubule reorganization augments IgE-independent/non-antigenic stimuli-induced mucosal mast cell degranulation, thereby contributing to the development of FA.Food allergy (FA) is a serious public health concern that is estimated to affect approximately 5% of children and 3-4% of adults in developed countries (18). The pathogenic mechanisms underlying FA are not fully understood despite the epidemic prevalence and its life-threatening potential, and there is neither a curative drug treatment nor an effective means of prevention (3). Therefore, a deeper understanding of the pathology of FA is needed.Mast cells play a central role as effector and conductor cells in the development of various allergic diseases via the release of various inflammatory mediators, such as proteases, eicosanoids, biogenic amines, cytokines and chemokines (1). High affinity IgE receptor (FcεRI)-mediated mast cell degranulation process can be divided into the following two process as the calcium-independent and microtubule-dependent translocation of granules to the plasma membrane and the calcium-dependent fusion of granules with the plasma membrane for exocytosis (14). Mast cells are classified as mucosal mast cells or connective tissue mast cells. It is well known that mucosal mast cells are morphologically, biochemically and functionally distinct from connective tissue mast cells. We have previously demonstrated that our murine FA model exhibits several features

Nociceptor Sensory Neuron–Immune Interactions in Pain and Inflammation

“…Nociceptor neurons may drive lung inflammation through their release of the neuropeptide VIP, which acts on the VPAC2 receptor expressed by Type 2 innate lymphoid cells (ILC2) to induce IL-5 production [42] (Figure 3d). Neuropeptides also potentiate degranulation of mast cells, key mediators of allergic inflammation [5,96]. Thus, silencing neurons may be a strategy to treat asthmatic lung inflammation.…”

Pain and immunity: implications for host defence

“…This contrasts to in other cell types, where substance P is detected by NK1R (also known as TACR1). Rodent mast cells also express receptors for CGRP, and CGRP can potentiate mast cell activation and degranulation 121,122 . CGRP-mediated vasodilation and mast cell de-granulation is a pathophysiological mechanism in mouse models of migraine 123 , although the physiological contribution of mast cell activation in human migraine remains less well understood 124 .…”

Morphological elucidation of short-chain fatty acid receptor GPR41-positive enteric sensory neurons in the colon of mice with dextran sulfate sodium-induced colitis

“…We already reported that CGRP-positive intrinsic sensory neurons, through neuro-immune interactions with mucosal mast cells, are deeply involved in the pathology of food allergies [ 12 , 21 , 22 ]. Furthermore, microbiota-driven crosstalk between muscularis macrophages and enteric neurons reportedly regulates gastrointestinal motility [ 23 ].…”