Role of neutrophil extracellular traps (NETs) in Inflammatory bowel disease

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Project Summary In 2020, approximately 1.6 million Americans were confirmed to have inflammatory bowel disease (IBD) and it is expected that as many as 70,000 new cases of IBD are diagnosed in the United States each year. IBD comprises of chronic, relapsing inflammatory disorders affecting the gastrointestinal (GI) tract, such as Crohn’s Disease and Ulcerative Colitis. Among various immune cells that participate in IBD, neutrophils are not only the first responder cell-type to inflammation, but also involved in limiting inflammation and facilitating wound repair. Of note, there is a dearth of literature on the mucoprotective role of the enzyme peptidyl arginine deiminase-4 (PAD4), whose predominant function is to facilitate the generation of citrullinated histone 3 (H3Cit) and the release of DNA as neutrophil extracellular traps (NETs). The overall goal of the research is to study the role PAD4 in inflammatory bowel disease (IBD). This proposal aims to systematically elucidate the role of PAD4- mediated release of H3Cit and NETs during IBD. Three specific aims are proposed, each of which investigates the molecular underpinnings by which PAD4 influence gut health and disease. The three aims are interrelated, independently achievable and would systematically characterize: (i) the role of NETs in murine models of IBD, (ii) the adverse consequence of PAD4-deficiency in potentiating the ‘spillover’ of neutrophil granule proteins and (iii) the significance of NETs in preventing bacterial encroachment on the mucosa, that otherwise can perpetuate intestinal inflammation.