P2X7 receptor blockade decreases inflammation,apoptosis,and enteric neuron loss during Clostridioides difficile toxin A-induced ileitis in mice  

作　　者：Ana A Q A Santos Deiziane V S Costa Danielle A Foschetti Antoniella S G Duarte Conceicao S Martins Pedro M G Soares Patricia Castelucci Gerly A C Brito 

机构地区：[1]Department of Morphology,School of Medicine,Federal University of Ceara,Fortaleza 60430-170,Ceara,Brazil [2]Department of Physiology and Pharmacology,School of Medicine,Federal University of Ceará,Fortaleza 60430-170,Ceara,Brazil [3]Department of Pathology and Legal Medicine,School of Medicine,Federal University of Ceara,Fortaleza 60430-170,Ceara,Brazil [4]Department of Morphology(UFC),Federal University of Ceara,Fortaleza 60430-170,Ceara,Brazil [5]Department of Anatomy,Institute of Biomedical Sciences,University of São Paulo,Sao Paulo 05508-270,Brazil [6]Department of Morphology,Federal University of Ceara,Fortaleza 60140-170,Ceara,Brazil

出　　处：《World Journal of Gastroenterology》2022年第30期4075-4088,共14页世界胃肠病学杂志（英文版）

基　　金：Supported by PRONEX CNPq/FUNCAP,No.PR2-0101-00060.01.00/15;Sao Paulo Research Foundation(FAPESP),No.2014/25927-2 and No.2018/07862-1.

摘　　要：Clostridioides difficile(C.difficile)is the most common pathogen causing health care-associated infections.C.difficile TcdA and TcdB have been shown to activate enteric neurons;however,what population of these cells is more profoundly influenced and the mechanism underlying these effects remain unknown.AIM To characterize a specific population of TcdA-affected myenteric neurons and investigate the role of the P2X7 receptor in TcdA-induced ileal inflammation,cell death,and the changes in the enteric nervous system in mice.METHODS Swiss mice were used to model TcdA-induced ileitis in ileal loops exposed to TcdA(50μg/Loop)for 4 h.To investigate the role of the P2X7 receptor,Brilliant Blue G(50 mg/kg,i.p.),which is a nonspecific P2X7 receptor antagonist,or A438079(0.7μg/mouse,i.p.),which is a competitive P2X7 receptor antagonist,were injected one hour prior to TcdA challenge.Ileal samples were collected to analyze the expression of the P2X7 receptor(by quantitative real-time polymerase chain reaction and immunohistochemistry),the population of myenteric enteric neurons(immunofluorescence),histological damage,intestinal inflammation,cell death(terminal deoxynucleotidyltransferasemediated dUTP-biotin nick end labeling),neuronal loss,and S100B synthesis(immunohistochemistry).RESULTS TcdA upregulated(P<0.05)the expression of the P2X7 receptor gene in the ileal tissues,increasing the level of this receptor in myenteric neurons compared to that in control mice.Comparison with the control mice indicated that TcdA promoted(P<0.05)the loss of myenteric calretinin+(Calr)and choline acetyltransferase+neurons and increased the number of nitrergic+and Calr+neurons expressing the P2X7 receptor.Blockade of the P2X7 receptor decreased TcdAinduced intestinal damage,cytokine release[interleukin(IL)-1β,IL-6,IL-8,and tumor necrosis factor-α],cell death,enteric neuron loss,and S100B synthesis in the mouse ileum.CONCLUSION Our findings demonstrated that TcdA induced the upregulation of the P2X7 receptor,which promoted enteric neuron l

关 键 词：Clostridioides difficile Clostridioides difficile toxin A P2X7 receptor Enteric nervous system Enteric neuron Enteric glia 

分 类 号：R574.53[医药卫生—消化系统]