G蛋白偶联受体120激动剂缓解炎症性肠病的T细胞免疫机制研究

The mechanisms by which gut microbiota regulates intestinal homeostasis and the pathogenesis of inflammatory bowel diseases (IBD) remain unclear. Increasing evidence suggest that the interactions between diet and the gut microbiota may play a critical role in promoting or alleviating intestinal inflammation. However, little is known about the mechanisms involved. Long-chain fatty acids (LCFA), the major components of dietary fat that are absorbed and sensed by host cells, provide important energy sources as dietary nutrients, and act as signaling molecules in various cellular processes. GPR120 (also known as free fatty acid receptor 4, FFAR4) has been identified recently as a bona fide receptor for LCFA, and has a critical role in various physiological homeostasis mechanisms such as adipogenesis . Its agonists have been suggested as therapeutic targets for diabetes, metabolic disorders and inflammatory diseases. Mice deficient in GPR120 are more susceptible to insulin resistance and higher expression of the genes connected to inflammation. GPR120 agonists have been further shown to inhibit proinflammatory cytokine production of DC and macrophages. However, the mechanisms involved are still largely unknown. It is also unknown if and how GPR120 regulates intestinal homeostasis through regulation of microbiota. Our preliminary data further show that GPR120 agonist promoted T cell IL-10, thereby indicating a crucial role of GPR120 in regulation of T cell function and intestinal inflammation. Taken together, the central hypothesis of this project is that GPR120 signaling inhibits T cell production of IL-10 through inducing expression of IRF1 and Blimp-1, which leads to preservation of intestinal immune homeostasis and inhibition of IBD.

炎症性肠病已经成为全球健康系统面临的巨大挑战，明确IBD的致病机制、研发新型IBD治疗药物迫在眉睫。G蛋白偶联受体在肠道粘膜中高表达，可以抑制炎症反应的发生；效应T细胞分泌IL-10，在调节胃肠道稳态、抑制炎症性肠病发生中起重要作用。前期研究结果提示在DSS诱导的小鼠结肠炎症模型中，GPR120激动剂通过分泌IL-10缓解结肠炎症。该课题提出如下假说：GPR120信号通路主要为诱导IRF-1和Blimp-1表达，促进T细胞分泌IL-10，从而维护胃肠道免疫稳态，抑制炎症性肠病。为了进一步阐明GPR120激动剂对效应T细胞的影响，本研究将通过多种动物实验模型、临床标本、细胞实验，明确GPR120激动剂预防及治疗IBD中的效果，阐明GPR120激动剂促进T细胞表达IL-10机制，阐释胃肠道微生物在通过GPR120激动剂抑制炎症的作用，以期为IBD的治疗提供新的治疗靶点。

G蛋白偶联受体(GPR)120是omega3脂肪酸(-3FA)的受体，参与具有抗炎功能的代谢综合征的调节。 本研究发现，在DSS诱导和肠道感染诱导的结肠炎症模型中，GPR120缺陷会导致更严重的结肠炎。 GPR120在CD4+ T细胞中高水平表达，小鼠特异性缺乏GPR120+ T细胞更易诱发重症结肠炎。 实验证明，转输GPR120基因缺陷CD4+ CD45Rbhi T细胞至Rag-/-小鼠体内诱导结肠炎，与转输野生型(WT)T细胞相比，易进展为重症结肠炎，其机制为小鼠肠道固有层IL-17+和IFN-ɣ+CD4+T细胞增多，IL-10+ T细胞减少。 GPR120激动剂CPDA预处理CD4+ T细胞，Blimp1表达上调和糖酵解增强，促进IL-10+T细胞分化成熟。 另外，与GPR120激动剂预处理WT CD4+T细胞相比，转输未经GPR120激动剂预处理Blimp1缺乏的Th1细胞,可诱导较轻的结肠炎。 接着，我们证实口服CPDA可以缓解小鼠肠道炎症。 因此，该研究发现GPR120通过调节肠道CD4+ T细胞的产生IL-10维持肠道稳态缓解结肠炎症，为炎症性肠病的治疗提供了新靶点。