Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance ofNippostrongylus brasiliensisthrough induction of T_H2 cytokines

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 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 upregulation of TH2 cytokines was attenuated and nematode clearance was delayed. In Chrm3(-/-) mice, TH2-dependent changes in small intestinal function including smooth muscle hypercontractility, 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.

Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice

“…The scores indicated degree of injury as follows: 0, absent; 1, mild; 2, moderate; 3, marked; 4, severe for each of the 5 categories, which were analyzed by category as well as combined for a total score of a maximum value of 20). In addition, morphometric measurements were conducted as described previously 31 . In brief, mucosal depth and smooth muscle thickness in the colon were measured in micrometers in digital brightfield images in ZEN Pro software (Carl Zeiss Microscopy, Thornwood, NY).…”

Prox1-positive cells monitor and sustain the murine intestinal epithelial cholinergic niche

“…Muscarinic receptors (M1R-M5R) signal via G αq/11 or G i/o and govern mucosal ion transport 23 , epithelial proliferation 7 , and barrier function 24 or immune host defense mechanisms 8 . Taking into consideration the reported turnover times for intestinal Paneth and endocrine cell types 25,26 , long-term treatment of WT mice with the nonselective muscarinic receptor antagonist scopolamine 7 was employed to investigate the role of muscarinic signaling on the intestinal epithelial cell differentiation.…”

Immunity to gastrointestinal nematode infections

“…Thus, the responsiveness of smooth muscle cells to neurotransmitters that control contraction via muscarinic receptors are important for N. brasiliensis expulsion. 193 Most of the available data on gut peristalsis during nematode infection are however highly correlative 73,102 and its importance remains to be established. Nevertheless, together these mechanisms effectively expel the invading parasite.…”