ABSTRACT
Recently, the involvement of the nervous system in the pathology of allergic diseases has attracted increasing interest. However, the precise pathophysiological role of enteric neurons in food allergies has not been elucidated. We report the presence of functional high-affinity IgE receptors (FcεRIs) in enteric neurons. FcεRI immunoreactivities were observed in approximately 70% of cholinergic myenteric neurons from choline acetyltransferase-eGFP mice. Furthermore, stimulation by IgE-antigen elevated intracellular Ca2+ concentration in isolated myenteric neurons from normal mice, suggesting that FcεRIs are capable of activating myenteric neurons. Additionally, the morphological investigation revealed that the majority of mucosal mast cells were in close proximity to enteric nerve fibers in the colonic mucosa of food allergy mice. Next, using a newly developed coculture system of isolated myenteric neurons and mucosal-type bone-marrow-derived mast cells (mBMMCs) with a calcium imaging system, we demonstrated that the stimulation of isolated myenteric neurons by veratridine caused the activation of mBMMCs, which was suppressed by the adenosine A3 receptor antagonist MRE 3008F20. Moreover, the expression of the adenosine A3 receptor gene was detected in mBMMCs. Therefore, in conclusion, it is suggested that, through interaction with mucosal mast cells, IgE-antigen-activated myenteric neurons play a pathological role in further exacerbating the pathology of food allergy.
Subject(s)
Cell Communication , Enteric Nervous System/physiopathology , Food Hypersensitivity/immunology , Food Hypersensitivity/physiopathology , Intestinal Mucosa/immunology , Intestinal Mucosa/physiopathology , Mast Cells/immunology , Neurons/pathology , Adenosine/pharmacology , Adenosine A3 Receptor Antagonists/pharmacology , Animals , Antigens/metabolism , Bone Marrow Cells/drug effects , Bone Marrow Cells/pathology , Cell Communication/drug effects , Cells, Cultured , Enteric Nervous System/drug effects , Enteric Nervous System/immunology , Intestinal Mucosa/drug effects , Intracellular Space/metabolism , Male , Mast Cells/drug effects , Mice, Inbred BALB C , Mice, Inbred C57BL , Models, Biological , Myenteric Plexus/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptor, Adenosine A3/genetics , Receptor, Adenosine A3/metabolism , Receptors, IgE/metabolismABSTRACT
Although the etiology of inflammatory bowel disease (IBD) remains unclear, it has generally been accepted that abnormalities in the intestinal immune system and dysbiosis of the gut microbiota are involved in the pathology of IBD. Recently, short-chain fatty acids (SCFAs) produced by gut microbiota were reported to maintain intestinal homeostasis through their receptors, such as GPR41. However, there are contradictory reports about the role of GPR41 in intestinal inflammation. Consequently, the roles of GPR41 in dysbiosis induced by intestinal inflammation remain unclear. Thus, we investigated the distribution of GPR41 in the colonic mucosa of mice with dextran sulfate sodium (DSS)-induced colitis. GPR41-immunoreactive fibrous structures were observed in the colonic lamina propria and muscularis layer of normal mice. In addition, GPR41-immunoreactive fibrous structures partly colocalized with calcitonin gene-related peptide (CGRP; a neurotransmitter of cholinergic enteric sensory neurons)-immunoreactive nerve fibers in the colonic lamina propria, indicating that GPR41 is expressed in cholinergic intrinsic sensory neurons. Furthermore, both GPR41-immunoreactivities and CGRP-immunoreactivities were significantly increased in the lamina propria of the colon in mice with DSS-induced colitis. Interestingly, GPR41-immunoreactivities were often found in close proximity to F4/80+ macrophages in the colonic mucosa of normal mice, and their frequency was elevated in the colonic mucosa of mice with DSS-induced colitis. Therefore, the crosstalk between SCFA-sensing intrinsic sensory neurons and macrophages might be involved in the pathology of acute colitis.