CGRP-Related Neuropeptide Adrenomedullin 2 Promotes Tissue-Protective ILC2 Responses and Limits Intestinal Inflammation

­­Neuro-immune circuits regulate innate and adaptive immunity at barrier surfaces, however the differential impact of these circuits on proinflammatory versus tissue-protective responses remains poorly defined. We identify that enteric neurons produce CGRP-related adrenomedullin 2 (ADM2), and identify a previously unrecognized role for the ADM2-ADM2 receptor pathway in promoting intestinal tissue-protective functions of group 2 innate lymphoid cells (ILC2s). Genomic or ILC2-intrinsic deletion of ADM2 receptor subunits resulted in a significant reduction in tissue-protective ILC2 responses, defective amphiregulin (AREG) production and increased susceptibility to intestinal damage and inflammation. Conversely, therapeutic delivery of recombinant ADM2 elicited tissue-protective AREG production in ILC2s and limited intestinal inflammation. Expression of genes encoding human ADM2 receptor (CALCRL and RAMP3) was altered in IBD patients and associated with reduced expression of AREG in ILC2s. Collectively, these findings identify that the ADM2-ADM2 receptor pathway can promote tissue-protective functions of ILC2s in the context of intestinal damage and inflammation.