Mechanisms of microbiota induced IL-23/Th17 immune responses in chronic colitis

慢性结肠炎中微生物群诱导 IL-23/Th17 免疫反应的机制

• 批准号: 237734245
• 负责人: Professor Dr. Markus F. Neurath
• 金额: --
• 依托单位: Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/237734245?language=en
• 关键词: Mechanisms; microbiota; induced; IL; 23

Complex regulatory mechanisms work together to maintain intestinal homeostasis, and a breakdown in these pathways may finally result in inflammatory bowel disease (IBD). Much of our present understanding of intestinal homeostasis is built around the concept that the microbiota continuously interacts with the intestinal immune system and that the microbiota composition regulates the fine equilibrium between pro-inflammatory and tolerogenic immune responses. However, whether disease related shifts in microbiota composition that were shown to occur in IBD directly cause disease or reflect the adaptation of bacterial communities to inflammation or host genotype related changes in the intestinal environment is still incompletely understood. Genetic polymorphisms in the IL-23R gene and other regions that encode proteins implicated in the IL-23/TH17 pathway in IBD as well as murine studies suggest that appropriate regulation of IL-23 dependent immune responses is critical for intestinal immune homeostasis. On the other hand the IL-23/TH17 axis may play a central role in protective immunity to gastrointestinal infections. In this project, we will mechanistically investigate the crosstalk between IL-23 producing cells, IL-23R+ immune cell populations, their effector cytokines and the commensal flora. An IL-23 reporter mouse strain will be used to analyze the spatiotemporal expression of IL-23 under germfree conditions and after re-colonization with conventional or defined microflora. Using a mouse model of IL-23 dependent spontaneous colitis, we will characterize the intestinal T cell and innate lymphoid cell (ILC) pool in intestinal tissues before and after onset of colitis; these results will be compared to the situation in IBD patients. In parallel, the compositional analysis of the intestinal microbiota by 16S rRNA metagenomic studies will help to characterize the microbiota/immune system interactions in the transition phase from healthy to inflammatory settings. Moreover, as the cytokines IL-17 and IL-22 that are particularly produced by TH17 cells and RORγt+ ILC in an IL-23 dependent manner are important regulators of antimicrobial peptide production in intestinal epithelial cells (IEC), we will determine how cytokine induced antimicrobial peptide production affects microbial composition and diversity in the gut. In line with this, we will analyze in models of infectious colitis, how IL-23 dependent production of antimicrobial factors in IEC contribute to physiological host responses to intestinal pathogens.

复杂的调节机制共同作用以维持肠道内稳态，这些途径的破坏可能最终导致炎症性肠病（IBD）。我们目前对肠道内稳态的许多理解都是围绕着这样的概念建立的，即微生物群持续地与肠道免疫系统相互作用，并且微生物群组成调节促炎性免疫应答和致耐受性免疫应答之间的良好平衡。然而，在IBD中发生的微生物群组成的疾病相关变化是否直接导致疾病或反映细菌群落对炎症或肠道环境中宿主基因型相关变化的适应仍不完全清楚。IL-23 R基因和编码IBD中IL-23/TH 17通路相关蛋白质的其他区域的遗传多态性以及小鼠研究表明，适当调节IL-23依赖性免疫应答对肠道免疫稳态至关重要。另一方面，IL-23/TH 17轴可能在对胃肠道感染的保护性免疫中起核心作用。 在这个项目中，我们将从机制上研究IL-23产生细胞，IL-23 R+免疫细胞群，其效应细胞因子和植物植物群之间的串扰。IL-23报告小鼠品系将用于分析在无菌条件下以及在用常规或确定的微生物群重新定殖后IL-23的时空表达。使用IL-23依赖性自发性结肠炎的小鼠模型，我们将表征结肠炎发作前后肠组织中的肠T细胞和先天性淋巴细胞（ILC）池;这些结果将与IBD患者的情况进行比较。同时，通过16 S rRNA宏基因组研究对肠道微生物群进行组成分析将有助于表征从健康到炎症环境过渡阶段的微生物群/免疫系统相互作用。此外，由于特别由TH 17细胞和RORγt+ ILC以IL-23依赖性方式产生的细胞因子IL-17和IL-22是肠上皮细胞（IEC）中抗菌肽产生的重要调节剂，我们将确定细胞因子诱导的抗菌肽产生如何影响肠道中的微生物组成和多样性。与此相一致，我们将在感染性结肠炎模型中分析IEC中抗菌因子的IL-23依赖性产生如何促进宿主对肠道病原体的生理反应。