The M3 Muscarinic Receptor Is Required for Optimal Adaptive Immunity to Helminth and Bacterial Infection

Darby et al. PLoS pathogens, 2015; 11.1: e1004636-e1004636.

Speaker: Ming-Yang Wu (吳明陽)                               Time: 14:00~15:00, May 27, 2015

Commentator: Dr. Wei-Chen Lin (林威辰 老師)        Place: Room 601

Abstract:

Acetylcholine (ACh) is a neurotransmitter that consists of two main classes of acetylcholine receptor (AChR), nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR). Cholinergic signaling can control local innate immune responses and suppress inflammation through nAChR^[1]. However,   the role of AChR in the adaptive immunity is largely unknown, especially mAChR. mAChR family contains five subtypes (M1-M5), and previous study showed M3R is significant expression on smooth muscle to increase muscle contraction that contribute to the immune response to expel Nippostrongylus brasiliensis^[2]. In this study, the author uses M3R deficient mice (M3R^-/-) and ex vivo CD4 T cell assays to investigate whether M3R will play a important role in protective immunity. M3R^-/- mice significantly lost the ability to launch effective adaptive immune response to primary and secondary infection, and CD4 T cell-associated protective cytokine response reduced in this defect. ACh can stimulate CD4 T cells from wild-type (WT) mice that infected with N.brasiliensis and muscarinic agonists, such asmuscarine and oxotremorine-M (oxo-M), all agonists enhanced their Th2 cytokines secretion, and muscarinic antagonists atropine and M3R-selective antagonists can block this effect. M3R^-/- mice infected with Salmonella typhimurium observed similar impairment in immunity. S.typhimurium infection induced a robust Th1 immune response, with production of IFN-γ by CD4 T cells critical for host protection and bacterial clearance. In the M3R^-/- mice, they observed higher bacterial loads, which again correlated with impaired CD4 T cell immune response. Similarly, ACh stimulated the lymphocytes from S.typhimurium-infected WT mice ex vivo and muscarinic agonists also enhanced IFN-γ secretion, and this effect blocked with muscarinic M3R-selective antagonists. Collectively, this results indicate that the magnitude and efficacy of the adaptive response to infection depends on cholinergic signaling via the M3R.

Reference:

1.    Wang H, et al. (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421: 384–388.

2.    Horsnell WG, et al. (2007) Delayed goblet cell hyperplasia, acetylcholine receptor expression, and worm expulsion in SMC-specific IL-4Ralpha-deficient mice. PLoS Pathog 3: e1.