Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of Nippostrongylus brasiliensis through induction of TH2 cytokines

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2016-07, Vol.311 (1), p.G130-G141
• Main Authors: McLean, Leon P, Smith, Allen, Cheung, Lumei, Urban, Jr, Joseph F, Sun, Rex, Grinchuk, Viktoriya, Desai, Neemesh, Zhao, Aiping, Raufman, Jean-Pierre, Shea-Donohue, Terez
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Cytokines - immunology; Cytokines - metabolism; Disease Models, Animal; Epithelial Biology and Secretion; Genetic Predisposition to Disease; Homeostasis; Host-Pathogen Interactions; Immunity, Mucosal; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - parasitology; Intestine, Small - immunology; Intestine, Small - metabolism; Intestine, Small - parasitology; Macrophage Activation; Macrophages - immunology; Macrophages - metabolism; Macrophages - parasitology; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Nippostrongylus - immunology; Nippostrongylus - pathogenicity; Phenotype; Receptor, Muscarinic M3 - deficiency; Receptor, Muscarinic M3 - genetics; Receptor, Muscarinic M3 - metabolism; Strongylida Infections - genetics; Strongylida Infections - immunology; Strongylida Infections - metabolism; Strongylida Infections - parasitology; Th2 Cells - immunology; Th2 Cells - metabolism; Th2 Cells - parasitology; Time Factors
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00461.2014

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.