A neuronal-epithelial circuit promotes intestinal immunity 2891

Abstract Description The intestinal epithelial lining provides a critical physical barrier to protect host tissues against environmental insults including dietary antigens, allergens, and microorganisms. Regulation of the host epithelial barrier is coordinated by signals from diverse inputs including immune and neuronal cells; however, how these signals are integrated remains unknown. Here, we identify a novel mechanism of neuro-epithelial communication by which pain-sensing TRPV1+ nociceptors alter the responses of intestinal tuft cells, specialized chemosensory epithelial cells known to promote type 2 immunity against parasites. We demonstrate that chemogenetic silencing of TRPV1+ nociceptors leads to reduced tuft cells and delayed Trichuris clearance. In contrast, activation of nociceptors leads to the rapid accumulation of tuft cells and accelerated clearance of the helminth Trichuris muris. Finally, we show that exogenous administration of the neuropeptide calcitonin gene-related peptide (CGRP), increased during nociceptor activation, can induce tuft cell responses both in vitro and in vivo, and that epithelial CGRP signaling contributes to anti-helminth immunity. Together, these results identify a neuronal-epithelial circuit as a critical upstream determinant of type 2 immunity and tissue adaptation and have important implications for inflammatory conditions associated with defects in the epithelial barrier, including asthma, allergy, and inflammatory bowel diseases (IBD). Funding Sources Supported by the NIH (DK126871, AI151599, AI095466, AI095608, AI142213, AR070116, AI172027, DK132244), the Cure for IBD, Weill Cornell Medicine Jill Roberts Institute, and the Sanders Family and the Rosanne H. Silbermann Foundation. This work is also supported by the Allen Discovery Center program, a Paul G. Allen Frontiers Group advised program of the Paul G. Allen Family Foundation. Topic Categories Mucosal and Regional Immunology (MUC)