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Inflamm Bowel Dis. 2015 Aug;21(8):1860-71. doi: 10.1097/MIB.0000000000000408.

Type 3 Muscarinic Receptors Contribute to Clearance of Citrobacter rodentium.

Author information

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.

PMID:
25985244
PMCID:
PMC4821008
DOI:
10.1097/MIB.0000000000000408
[Indexed for MEDLINE]
Free PMC Article

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