Intestinal Epithelial Wnt Signaling Mediates Acetylcholine-Triggered Host Defense against Infection

Publication date: 15 May 2018
Source:Immunity, Volume 48, Issue 5
Author(s): Sid Ahmed Labed, Khursheed A. Wani, Sakthimala Jagadeesan, Abdul Hakkim, Mehran Najibi, Javier Elbio Irazoqui
Regulated antimicrobial peptide expression in the intestinal epithelium is key to defense against infection and to microbiota homeostasis. Understanding the mechanisms that regulate such expression is necessary for understanding immune homeostasis and inflammatory disease and for developing safe and effective therapies. We used Caenorhabditis elegans in a preclinical approach to discover mechanisms of antimicrobial gene expression control in the intestinal epithelium. We found an unexpected role for the cholinergic nervous system. Infection-induced acetylcholine release from neurons stimulated muscarinic signaling in the epithelium, driving downstream induction of Wnt expression in the same tissue. Wnt induction activated the epithelial canonical Wnt pathway, resulting in the expression of C-type lectin and lysozyme genes that enhanced host defense. Furthermore, the muscarinic and Wnt pathways are linked by conserved transcription factors. These results reveal a tight connection between the nervous system and the intestinal epithelium, with important implications for host defense, immune homeostasis, and cancer.

Graphical abstract

Teaser

How intestinal epithelial antimicrobial defense functions are regulated is poorly understood. Using Caenorhabditis elegans, Labed et al. found infection-triggered neuronal acetylcholine release, driving intestinal defense gene expression via conserved muscarinic and Wnt pathways. This newly identified pathway may be relevant to the microbiota-gut-brain axis and immune homeostasis in humans.


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