Enteric nervous system-macrophage interactions in Hirschsprung-associated enterocolitis

Abstract/Project Summary: The gut is richly innervated by a dense network of intrinsic neurons and glia called the enteric nervous system (ENS). The ENS controls most aspects of bowel function including motility, blood flow, epithelial function, and immune cell activities. In 1:5000 children the ENS is missing from the distal bowel, a birth defect called Hirschsprung disease (HSCR). Children with HSCR are prone to HSCR associated enterocolitis (HAEC), a life-threatening colon inflammation. Although there are treatments for HAEC, many children have ongoing symptoms and the mechanisms underlying the enterocolitis remains poorly understood. In particular, how the absence of the ENS affects local immune cells and mechanisms of ENS-immune cell interactions are largely unexplored. Preliminary results in our murine HSCR model reveal increased macrophage infiltration of the distal colon that lacks ENS and changes in macrophage morphology that suggest altered macrophage function and roles for macrophage in colitis of the HSCR bowel. To find new ways to prevent HAEC, we will test the hypothesis that bowel macrophage phenotype changes in response to vasoactive intestinal peptide (VIP) or the absence of VIP signaling. VIP is an abundant ENS neurotransmitter that induces anti-inflammatory effects in diverse immune cell subtypes. We also will determine if reducing macrophage abundance or skewing macrophage toward an anti-inflammatory phenotype will reduce colitis severity in a HSCR model. These studies will provide new insight into neuro-immune interactions in the context of a HSCR disease model, and these results may suggest new strategies to treat or prevent HAEC.