Cytokine mediated mechanisms In the immunopathogenesis of inflammatory bowel diseases

在IBD患者的炎症发作期间，各种细胞类型产生了大量的细胞因子。促炎细胞因子启动并维持炎症过程，抗炎细胞因子控制肠道免疫反应并抑制炎症。直到最近，由非造血细胞如IL-33分泌的组织调节细胞因子才在屏障完整性的建立和肠道炎症的背景下成为关键的先天参与者。细胞因子IL-33在IBD中强烈上调。然而，研究是相互矛盾的，这种警报样蛋白在IBD背景下的确切作用仍有待充分表征。来自文献的数据以及我们自己的初步数据表明，IL-33可能通过协调不同细胞类型（如先天淋巴样细胞（ILC）和肠上皮细胞（lEC））的细胞功能来保护肠道。因此，我们旨在分析IL-33在肠道炎症背景下对不同肠细胞区室的细胞特异性功能。基于初步数据，我们将研究IL-33在小鼠和IBD患者肠道炎症过程中如何调节lEC和II型先天淋巴样细胞（ILC2）的功能。最后，我们将探讨IL-33是否以及如何参与ILC2 - lEC细胞串扰。总之，我们的目标是更好地了解IL-33功能的分子机制，以确定肠道保护途径，从而为未来的治疗干预提供目标。

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.