Epithelial-derived mediators of neutrophil infiltration in the intestine

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DESCRIPTION (provided by applicant): The human intestine is home to a continuous balancing act between the host immune response, the large population of resident bacteria, and the thin epithelial layer that separates them. Disruptions in this fine balance lead to intestinal inflammation, a significant cause of morbidity and mortality worldwide. The idiopathic inflammatory bowel diseases (IBD) impose a significant health and monetary burden in the developed world, with roughly 1 in 200 people in the US affected. In the developing world, infection with microbial pathogens leads to about two billion cases of diarrheal disease annually and 1.5 million deaths, primarily among children. Diarrheal pathogens such as Salmonella Typhimurium cause inflammatory diarrhea that mimics several clinical hallmarks of IBD including massive neutrophil infiltration into the intestine. Understanding the shared mechanisms that drive neutrophil infiltration during disease is therefore of critical importance in public health. Hepoxilin A3 (HXA3) is a lipid secreted from the apical surface of Salmonella- infected epithelial cells that has been identified as a crucial and specific mediator of neutrophil transepithelial migration in the intestine. HXA3 also drives neutrophil infiltration during intestial inflammation triggered by a variety of stimuli as well as during lung inflammation. In addition, we have recently identified an activity secreted by uninfected epithelial cells that inhibits HXA3-mediated migration, which we refer to as AMEND. We hypothesize that the balance between AMEND and HXA3 activity in the intestine regulates the homeostatic set point that must be overcome for the induction of intestinal inflammation. In this application we seek to further understand the interaction between HXA3 and neutrophils, and to investigate the mechanisms by which AMEND regulates HXA3 activity during homeostasis and disease. We will integrate findings in vitro and in vivo to define precise mechanisms of HXA3 and AMEND function during Salmonella infection, and will broaden the applicability of these findings by investigating the regulation of HXA3 activity by AMEND in DSS colitis and T cell transfer, two established mouse models of non-infectious colitis. Identification of the HXA3 receptor will provide a major conceptual advance in the field and identify a potential therapeutic target in inflammatory disease. Similarly, identifying the mechanism(s) by which AMEND regulates HXA3-mediated inflammation will highlight pathways to target for therapeutic intervention. Current therapies for IBD suffer from damaging sequelae and an inability to prevent relapses, with surgical intervention eventually required in 35-40% of ulcerative colitis patients and 70-80% of Crohn's disease patients. Targeting local inflammatory responses rather than systemic therapies may help to reduce damaging sequelae, and directing therapies to block the early steps in initiation of inflammation may have better outcomes in preventing relapse. Furthermore, the studies proposed here will contribute greatly to understanding the basic biology of the epithelium and its ability to control neutrophil recruitment, opening up further research avenues in intestinal biology.