Modulation of the Intestinal Immune Response in Necrotizing Enterocolitis

Project Summary/Abstract

Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants
and is characterized by an uncontrolled inflammatory response. The lack of understanding of the mechanisms
that regulate the vicious inflammatory cascade, the inability to determine which infants are susceptible to NEC
and a lack of therapeutic targets all contribute to the persistently high mortality rate. The goals of the
proposed research are to determine the mechanisms that regulate the pathologic immune response
during NEC and use this knowledge to design novel epithelial-­or immune-­specific strategies for this
devastating disease. Our laboratory has recently discovered that the interleukin-­22 (IL-­22) signaling pathway
plays a critical role in attenuating the inflammatory response during NEC, as mice lacking the receptor for IL-­22
(IL-­22Ra1) on the intestinal epithelium demonstrate accelerated mortality in a neonatal mouse model of NEC-­
like intestinal injury. We demonstrate that mice subjected to experimental NEC develop gross evidence of
small intestinal ischemia and necrosis, that can be completely rescued in mice with intact IL-­22 signaling by
administering recombinant IL-­22. In seeking to determine the mechanisms mediating this protection, we have
demonstrated that treatment with recombinant IL-­22 decreases the pro-­inflammatory Th17 lymphocytic
infiltrate, which we have shown contributes to NEC pathogenesis. Furthermore, we also determined that IL-­22
signaling is important in the regulation of intestinal stem cell differentiation, as mice deficient in IL-­22Ra1 in the
intestine demonstrate an abnormally profound phenotype characterized by decreased numbers of secretory
cells in the intestine as well as decreased expression of critical genes involved in intestinal stem cell
development and host defense. Based on these findings, we hypothesize that IL-­22 signaling through the
receptor IL-­22Ra1 attenuates NEC by 1) enhancing intestinal stem cell function, 2) increasing goblet cell
differentiation and 3) shifting the immune cell repertoire towards an anti-­inflammatory phenotype. We will
complete our aims of this project by bringing together a multi-­disciplinary team with expertise in epithelial
biology, mucosal immunology, mass cytometry, next-­generation sequencing, high-­resolution confocal and
intravital microscopy as well as microfluidics and engineering for the derivation of in vitro models of human
intestinal function using gut-­on-­a-­chip devices. These studies will make a significant conceptual advance in
understanding the signaling pathways involved in attenuating NEC, explaining the unique susceptibility of the
premature infant to NEC based on a defect in IL-­22 signaling, and we will evaluate a novel therapeutic strategy
for NEC by introducing the anti-­inflammatory cytokine IL-­22 in the intestinal milieu.