Inflammatory bowel diseases, which include both ulcerative colitis and Crohn's disease, are estimated to affect 3 million Americans, and the number of people living with IBD continues to rise. Currently available medications are costly, ineffective for some patients, and associated with serious risks including opportunistic infections, bone marrow suppression, hepatic inflammation, pancreatitis, and cancer. Thus, there is an urgent need to improve our understanding of modulators of intestinal inflammation and repair in order to identify novel therapeutic targets for the treatment of IBD. Innate lymphoid cells (ILCs) are a relatively-recently characterized family of immune cells that are enriched at barrier surfaces and modulate inflammation in response to cytokine and microbial signals. In particular, group 2 ILCs (ILC2s) sense alarmins and cytokines such as IL-25, IL-33, and TSLP, can be activated by the nervous system, and produce type 2 cytokines that promote anti-helminth immunity and allergic inflammation. Furthermore, our lab has shown that ILC2s also exert tissue-protective functions via secretion of the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG), resulting in amelioration of tissue damage following intestinal injury. In new preliminary studies presented here, we show that expression of the neuropeptide, neuromedin U (NMU), is increased during intestinal inflammation in mice, and lack of endogenous NMU results in more severe disease in a model of chemical-induced intestinal damage and inflammation. Conversely, therapeutic administration of NMU results in upregulation of ILC2- derived AREG and ameliorates chemical-induced intestinal damage. Furthermore, similar to in inflamed murine intestines, NMU expression is also elevated in IBD patient biopsies, and the receptor for NMU is detected on human colonic ILCs. Based on our new preliminary data, we hypothesize that enteric neuron-derived NMU activates the tissue-protective functions of ILC2s. We propose to generate a detailed understanding of how NMU mediates tissue protection in both murine models of intestinal inflammation and human IBD.
In Aim 1, we will test the hypothesis that during intestinal injury and repair, expression, cellular sources, and spatial pattern of NMU expression are altered. We will also test the role of endogenous enteric-derived NMU in maintaining tissue homeostasis.
In Aim 2, we will employ novel reporter mice to directly test the cellular and molecular mechanism by which NMU mediates tissue protection.
In Aim 3, we will define the NMU-NMUR1 axis in the healthy human intestine and determine how alterations in NMU-NMUR1 signaling correlate with clinical and endoscopic measures of IBD disease activity. In addition to uncovering fundamental and novel neuropeptide biology and their unique roles in IBD, these studies will provide preclinical justification for development of novel therapeutics to target this pathway.
Inflammatory bowel disease is a chronic illness that represents a significant public health and economic burden, and there is an urgent need to improve our understanding of modulators of intestinal inflammation in order to identify novel therapeutic targets. Recent studies from our lab have demonstrated that specialized immune cells known as group 2 innate lymphoid cells (ILC2s) respond to neuronal-derived signals to promote expulsion of intestinal parasites, but whether or not these same signals activate the tissue protective functions of these cells is unclear. The focus of this proposal is to dissect the role of this neuro-immune signaling pathway in the regulation of intestinal inflammation.
