title: Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of Nippostrongylus brasiliensis through induction of TH2 cytokines.
abstract: Despite increased appreciation for the role of nicotinic receptors in the modulation of and response to inflammation, the contribution of muscarinic receptors to mucosal homeostasis, clearance of enteric pathogens, and modulation of immune cell function remains relatively undefined. Uninfected and Nippostrongylus brasiliensis-infected wild-type and type 3 muscarinic receptor (M3R)-deficient (Chrm3(-/-)) mice were studied to determine the contribution of M3R to mucosal homeostasis as well as host defense against the TH2-eliciting enteric nematode N. brasiliensis Intestinal permeability and expression of TH1/TH17 cytokines were increased in uninfected Chrm3(-/-) small intestine. Notably, in Chrm3(-/-) mice infected with N. brasiliensis, small intestinal upregulation of TH2 cytokines was attenuated and nematode clearance was delayed. In Chrm3(-/-) mice, TH2-dependent changes in small intestinal function including smooth muscle hypercontractility, increased epithelial permeability, decreased epithelial secretion and absorption, and goblet cell expansion were absent despite N. brasiliensis infection. These findings identify an important role for M3R in host defense and clearance of N. brasiliensis, and support the expanding role of cholinergic muscarinic receptors in maintaining mucosal homeostasis.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland;
authors.forename: Leon P
authors.initials: LP
authors.lastname: McLean
authors.affiliation: Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, Maryland; and.
authors.forename: Allen
authors.initials: A
authors.lastname: Smith
authors.affiliation: Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, Maryland; and.
authors.forename: Lumei
authors.initials: L
authors.lastname: Cheung
authors.affiliation: Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, Maryland; and.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Urban
authors.affiliation: Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Rex
authors.initials: R
authors.lastname: Sun
authors.affiliation: Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Grinchuk
authors.affiliation: Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Neemesh
authors.initials: N
authors.lastname: Desai
authors.affiliation: Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Aiping
authors.initials: A
authors.lastname: Zhao
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland;
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Raufman
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland; Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland tdonohue@som.umaryland.edu.
authors.forename: Terez
authors.initials: T
authors.lastname: Shea-Donohue
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006706:Homeostasis; D054884:Host-Pathogen Interactions; D018928:Immunity, Mucosal; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000469:parasitology; D007421:Intestine, Small / Q000276:immunology / Q000378:metabolism* / Q000469:parasitology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009559:Nippostrongylus / Q000276:immunology / Q000472:pathogenicity*; D010641:Phenotype; D043587:Receptor, Muscarinic M3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017206:Strongylida Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000469:parasitology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism* / Q000469:parasitology; D013997:Time Factors
chemical_list: D016207:Cytokines; D043587:Receptor, Muscarinic M3
keywords: Nippostrongylus brasiliensis; TH2 cytokines; host defense; mucosal homeostasis; muscarinic receptor