Adaptive Immune Regulation of Enteric Neurogenesis Directs Intestinal Inflammation

About This Grant

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 have demonstrated that the peripheral and enteric nervous systems regulate intestinal immunity to infection and inflammation via complex neuro-immune circuits, including the production of neuropeptides such as calcitonin gene-related peptide (CGRP) and adrenomedullin 2 (ADM2) that directly regulate inflammation and restore tissue homeostasis in the gastrointestinal mucosa. However, little is known about whether and how these tissue protective enteric neurons are generated and regulated during the pathogenesis of IBD. In new preliminary data I demonstrate a new neuro-immune interaction wherein the enteric nervous system undergoes neurogenesis which is immunologically regulated during recovery from intestinal damage and inflammation. Newly generated neurons were found to highly express CGRP and ADM2. During recovery from intestinal inflammation, IL-17RA expression was enriched in enteric neurons, coinciding with the recruitment of IL-17A–producing CD4⁺ T cells to the colonic enteric nervous system. Further, mice with neuron- intrinsic deficiency in IL-17RA expression exhibit impaired neurogenesis and exacerbated disease severity compared to control mice with intact neuronal IL-17A signaling. Based on our new preliminary data, we hypothesize that the IL-17RA-IL-17A pathway is a previously unrecognized neuronal circuit that induces colonic enteric neurogenesis to promote tissue protection in the context of intestinal inflammation. We propose to generate a detailed understanding of how the IL-17RA-IL-17A axis promotes enteric neurogenesis and mediates tissue protection in murine models of intestinal inflammation. In Aim 1, we will test the hypothesis that the generation of new CGRP and ADM2 expressing enteric neurons are modulated during homeostasis and intestinal inflammation. Further we will identify the contribution of the microbiota to the generation and maintenance of CGRP and ADM2 expressing neurons in the colon under normal and inflammatory conditions. In Aim 2, we will use viral and genetic mouse models to selectively delete IL-17RA in enteric neurons and IL- 17A in CD4+ T cells, respectively, to investigate how the immune system regulates enteric neurogenesis during development and in response to intestinal damage and inflammation. In addition to uncovering fundamental and novel neuro-immune circuits and its roles in the pathogenesis of IBD, these studies could provide further insights to support the development of novel therapeutics that target the enteric nervous system.