Leon P McLean1, Allen Smith, Lumei Cheung, Rex Sun, Viktoriya Grinchuk, Tim Vanuytsel, Neemesh Desai, Joseph F Urban, Aiping Zhao, Jean-Pierre Raufman, Terez Shea-Donohue. 1. *Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland; †United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, Maryland; ‡Department of Radiation Oncology, Division of Translational Radiation Sciences, University of Maryland School of Medicine, Baltimore, Maryland; and §Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.
Abstract
BACKGROUND: The role of muscarinic receptors in mucosal homeostasis, response to enteric pathogens, and modulation of immune cell function is undefined. METHODS: The contribution of type 3 muscarinic receptors (M3R) to mucosal homeostasis within the colon and host defense against Citrobacter rodentium was determined in uninfected and C. rodentium-infected WT and M3R-deficient (Chrm3) mice. In addition, WT and Chrm3 bone marrow-derived macrophages were studied to determine the ability of M3R to modulate macrophage phenotype and function. RESULTS: In Chrm3 mice, clearance of C. rodentium was delayed despite an amplified TH1/TH17 response. Delayed clearance of C. rodentium from Chrm3 mice was associated with prolonged adherence of bacteria to colonic mucosa, decreased goblet cell number, and decreased mucin 2 gene expression. Treatment of bone marrow-derived macrophages with bethanechol, a muscarinic-selective agonist, induced a classically activated macrophage phenotype, which was dependent on M3R expression. Chrm3 bone marrow-derived macrophages retained their ability to attain a classically activated macrophage phenotype when treated with the TH1 cytokine IFN-γ. CONCLUSIONS: In Chrm3 mice, mucin production is attenuated and is associated with prolonged adherence of C. rodentium to colonic mucosa. The immune response, as characterized by production of TH1/TH17 cytokines, in C. rodentium-infected Chrm3 mice is intact. In addition, M3R activity promotes the development of classically activated macrophages. Our data establish a role for M3R in host defense against C. rodentium through effects on goblet cell mucus production and in the modulation of macrophage phenotype and function.
BACKGROUND: The role of muscarinic receptors in mucosal homeostasis, response to enteric pathogens, and modulation of immune cell function is undefined. METHODS: The contribution of type 3 muscarinic receptors (M3R) to mucosal homeostasis within the colon and host defense against Citrobacter rodentium was determined in uninfected and C. rodentium-infected WT and M3R-deficient (Chrm3) mice. In addition, WT and Chrm3 bone marrow-derived macrophages were studied to determine the ability of M3R to modulate macrophage phenotype and function. RESULTS: In Chrm3mice, clearance of C. rodentium was delayed despite an amplified TH1/TH17 response. Delayed clearance of C. rodentium from Chrm3mice was associated with prolonged adherence of bacteria to colonic mucosa, decreased goblet cell number, and decreased mucin 2 gene expression. Treatment of bone marrow-derived macrophages with bethanechol, a muscarinic-selective agonist, induced a classically activated macrophage phenotype, which was dependent on M3R expression. Chrm3 bone marrow-derived macrophages retained their ability to attain a classically activated macrophage phenotype when treated with the TH1 cytokine IFN-γ. CONCLUSIONS: In Chrm3mice, mucin production is attenuated and is associated with prolonged adherence of C. rodentium to colonic mucosa. The immune response, as characterized by production of TH1/TH17 cytokines, in C. rodentium-infected Chrm3mice is intact. In addition, M3R activity promotes the development of classically activated macrophages. Our data establish a role for M3R in host defense against C. rodentium through effects on goblet cell mucus production and in the modulation of macrophage phenotype and function.
Authors: M Wlodarska; B Willing; K M Keeney; A Menendez; K S Bergstrom; N Gill; S L Russell; B A Vallance; B B Finlay Journal: Infect Immun Date: 2011-02-14 Impact factor: 3.441
Authors: Kathleen B Madden; Karla Au Yeung; Aiping Zhao; William C Gause; Fred D Finkelman; Ildy M Katona; Joseph F Urban; Terez Shea-Donohue Journal: J Immunol Date: 2004-05-01 Impact factor: 5.422
Authors: Frans O The; Guy E Boeckxstaens; Susanne A Snoek; Jenna L Cash; Roel Bennink; Gregory J Larosa; Rene M van den Wijngaard; David R Greaves; Wouter J de Jonge Journal: Gastroenterology Date: 2007-07-25 Impact factor: 22.682
Authors: Justin M Chan; Ganive Bhinder; Ho Pan Sham; Natasha Ryz; Tina Huang; Kirk S Bergstrom; Bruce A Vallance Journal: Infect Immun Date: 2013-10-07 Impact factor: 3.441
Authors: Sumaira Z Hasnain; Huaqing Wang; Jean-Eric Ghia; Nihal Haq; Yikang Deng; Anna Velcich; Richard K Grencis; David J Thornton; Waliul I Khan Journal: Gastroenterology Date: 2010-02-04 Impact factor: 22.682
Authors: Sumaira Z Hasnain; Christopher M Evans; Michelle Roy; Amanda L Gallagher; Kristen N Kindrachuk; Luke Barron; Burton F Dickey; Mark S Wilson; Thomas A Wynn; Richard K Grencis; David J Thornton Journal: J Exp Med Date: 2011-04-18 Impact factor: 14.307
Authors: Leon P McLean; Allen Smith; Lumei Cheung; Joseph F Urban; Rex Sun; Viktoriya Grinchuk; Neemesh Desai; Aiping Zhao; Jean-Pierre Raufman; Terez Shea-Donohue Journal: Am J Physiol Gastrointest Liver Physiol Date: 2016-05-12 Impact factor: 4.052
Authors: Elise L Ma; Allen D Smith; Neemesh Desai; Lumei Cheung; Marie Hanscom; Bogdan A Stoica; David J Loane; Terez Shea-Donohue; Alan I Faden Journal: Brain Behav Immun Date: 2017-07-01 Impact factor: 7.217