Abstract
The prevalence of food allergy (FA) has increased in developed countries over the past few decades. However, no effective drug therapies are currently available. Therefore, we investigated cholinergic anti-inflammatory pathway as a regulatory system to ameliorate disrupted mucosal immune homeostasis in the gut based on the pathophysiological elucidation of mucosal mast cells (MMCs) in a murine FA model. BALB/c mice sensitized with ovalbumin received repeated oral ovalbumin for the development of FA. FA mice developed severe allergic diarrhea and exhibited enhanced type 2 helper T (Th2) cell immune responses in both systemic immunity and mucosal immunity, along with MMCs hyperplasia in the colon. MMCs were localized primarily in the strategic position of the mucosal epithelium. Furthermore, the allergic symptoms did not develop in p85α disrupted phosphoinositide-3 kinase-deficient mice that lacked mast cells in the gut. Vagal stimulation by 2-deoxy-D-glucose and drug treatment with nicotinic ACh receptor (nAChR) agonists (nicotine and α7 nAChR agonist GTS-21) alleviated the allergic symptoms in the FA mice. Nicotine treatment suppressed MMCs hyperplasia, enhanced MPO and upregulated mRNA expression of Th1 and Th2 cytokines in the FA mice colon. MMCs, which are negatively regulated by α7 nAChRs, were often located in close proximity to cholinergic CGRP-immunoreactive nerve fibers in the FA mice colon. The present results reveal that the cholinergic neuroimmune interaction via α7 nAChRs on MMCs is largely involved in maintaining intestinal immune homeostasis and can be a target for a new therapy against mucosal immune diseases with homeostatic disturbances such as FA.
Highlights
Food allergy (FA) is an abnormal immunologic reaction to food proteins, and its prevalence has increased in developed countries over the past few decades
We have demonstrated that a7 nicotinic ACh receptor (nAChR) are expressed in murine bone marrow-derived mast cells (mBMMCs) and that the stimulation of a7 nAChRs can negatively regulate the activation of mBMMCs [17]
We provide evidence that mucosal mast cells (MMCs) are primarily responsible for the pathology of the FA model and that the cholinergic neuro-immune interaction via a7 nAChRs on MMCs play a crucial role in controlling pathological immune activation to restore the homeostasis in the intestine
Summary
Food allergy (FA) is an abnormal immunologic reaction to food proteins, and its prevalence has increased in developed countries over the past few decades. The activation of mast cells results in the release of various inflammatory mediators, such as proteases, eicosanoids, biogenic amines, cytokines and chemokines [2]. Despite their strategic location in the mucosa of the intestinal microenvironment, the role of mast cells in FA has not been well investigated. Mast cells and nerves are assumed to communicate bilaterally to modulate neuro-physiological effects and mast cell functions [12], which suggests that the neuro-immune interaction may be involved in the pathology of allergic diseases. An elucidation of the cholinergic regulatory pathway has provided new concepts in understanding and treating FA
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