Location: Diet, Genomics and Immunology LaboratoryTitle: Type 3 Muscarinic Receptors Contribute to Clearance of Citrobacter rodentium
|MCLEAN, L - University Of Maryland|
|CHEUNG, L - University Of Maryland|
|SUN, R - University Of Maryland|
|GRINCHUK, V - University Of Maryland|
|VANUYTSEL, T - University Of Maryland|
|DESAI, N - University Of Maryland|
|ZHAO, A - University Of Maryland|
|RAUFMAN, J - University Of Maryland|
|SHEA-DONOHUE, T - University Of Maryland|
Submitted to: Inflammatory Bowel Diseases
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/1/2015
Publication Date: 5/15/2015
Citation: Mclean, L.P., Smith, A.D., Cheung, L., Sun, R., Grinchuk, V., Vanuytsel, T., Desai, N., Urban Jr, J.F., Zhao, A., Raufman, J.P., Shea-Donohue, T. 2015. Type 3 Muscarinic Receptors Contribute to Clearance of Citrobacter rodentium. Inflammatory Bowel Diseases. DOI: 10.1097/MIB.0000000000000408.
Interpretive Summary: Cholinergic receptors on immune cells respond to vagus nerve neurotransmitters by the production of inflammatory proteins. There are also nerves in the intestinal tissues that are close to inflammatory cells that suggest communication via “neuro-immune” links that can alter the function of cells directly involved in inflammatory responses to infection. This interaction can be modeled in experimental mice infected with Citrobacter rodentium, a gram-negative attaching/effacing bacterium that evokes a strong immune response and serves as a model for Escherichia coli food borne infection in humans and livestock. The current study was designed to investigate the role of a type of cholinergic receptor called M3R in host defense against bacterial infection in the intestine. The results showed that M3R activity does not affect a response by immune T cells, but does alter clearance of the bacteria from the intestine by attenuating mucus production by intestinal goblet cells, and the level of activation of inflammatory cells called intestinal macrophages that can destroy the bacteria. The work is important to scientists that study how regulatory circuits that control inflammation and infection are also affected by nerves and their products.
Technical Abstract: Although the alpha 7 nicotinic receptor exerts anti-inflammatory effects on immune cells, the role of muscarinic receptors in mucosal homeostasis, response to enteric pathogens, and modulation of immune cell function is undefined. The contribution of type 3 muscarinic receptor (M3R) to mucosal homeostasis within the colon and host defense against C. rodentium was determined in uninfected and Citrobacter rodentium-infected WT and M3R-deficient (Chrm3-/-) mice. In addition, WT and Chrm3-/- bone marrow-derived macrophages (BMDM) were studied to determine the ability of M3R to modulate macrophage phenotype and function. In Chrm3-/- mice clearance of C. rodentium was delayed; however, C. rodentium-infected Chrm3-/- mice had 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 BMDM with bethanechol, a muscarinic-selective agonist, induced a classically activated macrophage phenotype, which was dependent on M3R expression. Chrm3-/- BMDM retained their ability to attain a classically activated macrophage phenotype when treated with the TH1 cytokine IFN-'. In Chrm3-/- mice, production of TH1/TH17 cytokines in response to C. rodentium infection is amplified; however, mucin production is attenuated and is associated with prolonged adherence of C. rodentium to colonic mucosa. In addition, M3R activity promotes the development of classically activated macrophages. Our data establish a role for M3R in host defense against C. rodentium and in the modulation of macrophage phenotype and function.