Anti-allergic role of cholinergic neuronal pathway via α7 nicotinic ACh receptors on mucosal mast cells in a murine food allergy model.
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.
Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Toyama, Japan.
Takeshi
T
Yamamoto
Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Toyama, Japan.
Toshihisa
T
Kodama
Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Toyama, Japan.
Jaemin
J
Lee
Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Toyama, Japan.
Naho
N
Utsunomiya
Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Toyama, Japan.
Shusaku
S
Hayashi
Department of Physical Therapy, Health Science University, Fujikawaguchiko, Yamanashi, Japan.
Hiroshi
H
Sakamoto
Department of Applied Biology, Kyoto Institute of Technology, Kyoto, Kyoto, Japan.
Hirofumi
H
Kuramoto
Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, Toyama, Toyama, Japan.
Makoto
M
Kadowaki
D000818:Animals; D059329:Cholinergic Neurons / Q000276:immunology*; D003106:Colon / Q000276:immunology / Q000294:innervation / Q000473:pathology; D005512:Food Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D018418:Th2 Cells / Q000276:immunology; D014630:Vagus Nerve / Q000473:pathology / Q000503:physiopathology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000502:physiology*
D064569:alpha7 Nicotinic Acetylcholine Receptor