title: Type 3 Muscarinic Receptors Contribute to Clearance of Citrobacter rodentium.
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.
authors.affiliation: *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.
authors.forename: Leon P
authors.initials: LP
authors.lastname: McLean
authors.forename: Allen
authors.initials: A
authors.lastname: Smith
authors.forename: Lumei
authors.initials: L
authors.lastname: Cheung
authors.forename: Rex
authors.initials: R
authors.lastname: Sun
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Grinchuk
authors.forename: Tim
authors.initials: T
authors.lastname: Vanuytsel
authors.forename: Neemesh
authors.initials: N
authors.lastname: Desai
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Urban
authors.forename: Aiping
authors.initials: A
authors.lastname: Zhao
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Raufman
authors.forename: Terez
authors.initials: T
authors.lastname: Shea-Donohue
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D044082:Citrobacter rodentium / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004756:Enterobacteriaceae Infections / Q000276:immunology / Q000382:microbiology* / Q000517:prevention & control*; D005260:Female; D005455:Fluorescent Antibody Technique; D020397:Goblet Cells / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D043587:Receptor, Muscarinic M3 / Q000502:physiology*
chemical_list: D016207:Cytokines; D009077:Mucins; D043587:Receptor, Muscarinic M3