Targeted modulation of neutrophil activity: impact on intestinal immunopathology

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The intestinal immune system encounters the challenge of remaining unresponsive to the commensal microflora and food antigens whilst being able to mount a rapid immune response upon facing pathogens. Four major components contribute to gut homeostasis, including the epithelium, immune cells, intestinal microbes, and dietary metabolites. The importance of a tight control of immune response is emphasized in the context of chronic auto-inflammatory bowel diseases (IBD), such as Crohn's disease (CD) and Ulcerative Colitis (UC), where an immune response against commensals becomes dis-regulated. While much of investigation into IBD has been focused on the peak of immunopathology driven by specific innate immune cells, called monocytes, and adaptive immune cells, called T helper (Th) cells, the first defining events in initiation of intestinal inflammation received less attention. Particularly, the specific role of another type of innate immune cells, called neutrophils, during colitis has not been clearly delineated. Neutrophils rapidly traverse the vascular endothelium to reach the intestinal lamina propria. Their presence in human colonic biopsies is considered to be a sign of active disease and is increasingly used as a secondary endpoint in clinical trials in UC. In both peripheral blood and mucosal tissue of IBD patients, they display altered phenotype and effector functions. Neutrophil activation was also reported to affect T cell populations, specifically influencing pathogenic Th cells. However, the extent of neutrophil contributions into the initiation and propagation of pathological intestinal inflammation, their interactions with other immune cells and immune-imprinting left on the tissue, remain largely unexplored. Our recent findings demonstrate that, despite limited residence times in tissues, neutrophils can tailor their properties to mount specific and intrinsically regulated inflammatory response. Moreover, we have identified key molecular regulators specifically controlling neutrophil maturation or effector functions. This project will examine the functional impact of controlled modulation of neutrophil activity on the immunopathology of intestinal inflammation using the recently generated unique tools, such as genetically modified in vitro and in vivo models, newly discovered chemical inhibitors etc, and cutting-edge imaging and single cell genomic approaches. This may lead to the development of a new class of therapeutic strategies, based on selective modulation of neutrophil biology, to combat pathological inflammation and associated inflammatory disorders, such as IBD.