Location: Diet, Genomics and Immunology LaboratoryTitle: Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of nippostrongylus brasiliensis through induction of Th2 cytokines
|MCLEAN, L - University Of Maryland|
|SUN, R - University Of Maryland|
|GRINCHUK, V - Maryland Aquatic Nurseries|
|DASAI - University Of Maryland|
|ZHAO, AIPING - University Of Maryland|
|RAUFMAN, J - University Of Maryland|
|SHEA-DONOHUE, T - University Of Maryland|
Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/1/2016
Publication Date: 5/12/2016
Citation: Mclean, L.P., Smith, A.D., Cheung, L., Urban Jr, J.F., Sun, R., Grinchuk, V., Dasai, Zhao, A., Raufman, J.P., Shea-Donohue, T. 2016. Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of nippostrongylus brasiliensis through induction of Th2 cytokines. American Journal of Physiology - Gastrointestinal and Liver Physiology. 311(1):G130-141. doi: 10.1152/ajpgi.00461.2014.
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 Nippostrongylus brasiliensis, a gastrointestinal nematode parasite that evokes a strong allergic-type immune response and serves as a model for parasitic worm infections 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 worm infection locally in the small intestine. The results showed that M3R activity affected the function of immune cells called T cells that limited production of protein messenger molecules or cytokines that reduced mucus production by intestinal goblet cells and changed the absorptive and secretory capacity of the intestine. These effects altered the efficiency of the immune response against the worm and resulted in a more long lasting infection. The work is important to scientists who study how regulatory circuits that control inflammation and infection are also affected by nerves and their products.
Technical Abstract: 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 (WT) 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 up-regulation of TH2 cytokines was attenuated and nematode clearance was delayed. In M3R-deficient mice, TH2-dependent changes in small intestinal function including smooth muscle hyper-contractility, 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.