Adrenomedullin 2 Regulates ILC2 Responses to Control Intestinal Inflammation

Weill Medical Coll Of Cornell Univ, New York NY

Investigators

Abstract

PROJECT SUMMARY Inflammatory bowel diseases (IBD), which include ulcerative colitis and Crohn's disease, are estimated to affect 3 million individuals in the United States, and the number of people living with IBD continues to rise. Currently available treatment options are ineffective for some patients, costly and pose serious long-term complications, such as opportunistic infections, autoimmunity, and cancer. Thus, there is an urgent need to improve our understanding of the modulators of intestinal inflammation and repair in order to identify novel therapeutic targets to treat and prevent IBD. Emerging studies from multiple groups have demonstrated that the peripheral and enteric nervous systems regulate intestinal immunity to infection and inflammation via complex neuro-immune circuits, including neuropeptides neuromedin U (NMU) and calcitonin gene-related peptide (CGRP) that directly regulate inflammation and restore tissue homeostasis in the gastrointestinal mucosa. However, little is known whether and how these immunomodulatory neuropeptides play a pivotal role in the pathogenesis of IBD. In new preliminary studies, we identified that adrenomedullin 2 (ADM2), an understudied neuropeptide hormone, was highly upregulated in inflamed intestines of both humans and mice. While ADM2 utilizes ADM1 receptor (ADM1R) and ADM2 receptor (ADM2R) for signal transduction, mice deficient in ADM2R exhibited significantly increased susceptibility to a murine model of intestinal damage and inflammation. Further, therapeutic administration of exogenous rADM2 peptide substantially ameliorated the disease while concomitantly inducing a population expansion of a tissue-protective group 2 innate lymphoid cells (ILC2s) in the colon. Based on our new preliminary data, we hypothesize that the ADM2-ADM2R pathway drives non-redundant ILC2 responses to limit inflammation and promote tissue protection in the intestine. We propose to generate a detailed understanding of how the ADM2-ADM2R axis mediates tissue protection in both murine models of intestinal inflammation and human IBD. In Aim 1, we will test the hypothesis that during intestinal damage and tissue protection enteric neurons modulate their expression of ADM2. Further we will utilize chemogenetic manipulation of ADM2-expressing neurons to test how this impacts intestinal inflammation. In Aim 2, we will employ a novel mouse model that allows ILC2-specific deletion of ADM2R to directly test if ILC2-intrinsic ADM2R signaling is required for ADM2 mediated tissue protection and test if AREG is the specific molecular mediator that confers intestinal tissue protection. In addition to uncovering fundamental and novel neuropeptide biology of ADM2 and its roles in the pathogenesis of IBD, these studies could provide further insights to support the development of novel therapeutics to target this pathway.