Cytokine mediated mechanisms In the immunopathogenesis of inflammatory bowel diseases

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Substantial amounts of cytokines are produced by various cell types during inflammatory flares in IBD patients. While proinflammatory cytokines initiate and sustain the inflammatory process, anti-inflammatory cytokines control intestinal immune responses and suppress inflammation. Only recently, tissue-regulatory cytokines secreted by non-hematopoletic cells such as IL-33 emerged as key innate players in the establishment of barrier Integrity and in the context of gut inflammation. The cytokine IL-33 is strongly upregulated in IBD. However, studies are conflicting and the precise role of this alarmin-like protein in the context of IBD remains to be fully characterized. Data from the literature as well as our own preliminary data indicate that IL-33 might be gut protective by orchestrating cellular functions in different cell types, such as innate lymphoid cells (ILC) and intestinal epithelial cells (lEC). We therefore aim to analyze the cell-specific functions of IL-33 on different intestinal cell compartments in the context of intestinal inflammation. Based on preliminary data, we will study, how IL-33 regulates lEC and type II innate lymphoid cell (ILC2) functions in the course of intestinal inflammation in mice as well as in IBD patients. Finally we will investigate if and how IL-33 is involved in ILC2 - lEC cellular crosstalk. In summary we aim at a better understanding of the molecular mechanisms of IL-33 function to identify gut protective pathways that could be targeted for future therapeutic intervention.