IL-25信号通路及其在溃疡性结肠炎中的作用机制研究

The incidence of inflammatory bowel disease (IBD) is increasing in China with urbanization and socioeconomic development. Population-based IBD epidemiological study in Guangdong of China suggests the incidence of IBD is similar to that in Japan and Hong Kong but lower than that in South Korea and Western countries. Uncerative colitis(UC) is one of the chronic IBD without a medical cure and with unknown etiology. Current research suggests that type 2 response is a major reason for the pathogenesis of UC. The most divergent member of the IL-17 family is IL-17E (IL-25); it is induced in airway epithelial cells in response to allergens, expressed in mouse T lymphocytes of the CD4+ subset with a Th2 cell profile and human innate effector eosinophils and basophils. IL-25 has been demonstrated as one of the major driver of type 2 responses,implicating in allergy, asthma and helminth immunity.We previously examined the cell-type specific role of IL-25-induced Act1-mediated signaling in protective immunity against helminth infection. We found that targeted Act1 deficiency in epithelial cells resulted in a marked delay in worm expulsion and abolished the expansion of the Lin-c-kit+ innate cell population in the mesenteric lymph node, lung and liver. Our results suggest that epithelial-specific Act1 mediates the expansion of the Lin-c-kit+ innate cell population through the positive feedback loop of IL-25, initiating the type 2 immunity against helminth infection. However,the role of IL-25 signaling in the pathogenesis of UC remains unknown. We thus hypothesize that IL-25 signaling is critical for the initiation of type 2 response in UC and for the pathogenesis of the disease. We'll test our hypothesis by using animal model of UC, UC patient samples and innate lymphoid cells as well. This study is to define the roles of IL-25 signaling in the pathogenesis of UC, thus may provide new therapeutic strategies for UC in the future.

溃疡性结肠炎（溃结）是炎性肠病的一种，其发病率近年来在我国呈上升趋势。已有的研究表明II型免疫反应在溃结的病理发生中起重要作用，但是关于其II型免疫反应产生的机制仍不清楚。IL-25是IL-17家族一员，是II型免疫反应的主要驱动者之一。我们的前期研究通过寄生虫感染的动物模型，发现上皮细胞来源的IL-25通过作用于上皮细胞形成一个IL-25产生的正反馈循环。IL-25诱导上皮细胞产生IL-25和IL-33，IL-25和IL-33 诱导II型固有淋巴样细胞的扩增，进而诱发II型免疫反应。然而，IL-25的信号转导途径及其在溃结中的作用机制目前还不知道。本项目假设IL-25在溃结的II型免疫反应中发挥重要作用。我们将通过动物模型、病人样品和以II型固有淋巴样细胞为细胞模型来研究IL-25诱导的信号通路及其在溃结中的作用机制。这一研究将为溃结的治疗提供新的思路。

a．揭示LKB1在肠炎和肠癌中的免疫学新机制：应用肠道上皮细胞特异性LKB1基因敲除（VillinCreLKB1fl/fl，简写为LKB1ΔIEC）小鼠，我们发现LKB1ΔIEC小鼠易发肠炎。研究发现LKB1△IEC小鼠在稳态情况下肠道上皮细胞IL-18及IL-18相关抗菌肽（AMP）的产生显著减少，且肠道菌群紊乱。同时，我们发现，LKB1ΔIEC小鼠显著增加的肠炎易感性可以通过同笼饲养实验传播给LKB1WT对照小鼠；综上所述，肠道上皮细胞中LKB1通过影响肠道菌群组成而抑制肠道炎症的发生。以上工作发表在Journal of Immunology。..b. 揭示LRRK2在炎症小体活化和机体抗感染的新机制：LRRK2基因遗传多态性与多种疾病相关，然而LRRK2的生理性功能仍不清楚。本研究证实LRRK2对NLRC4炎症小体的活化是必需的。在机制研究方面，发现S. Typhimurium感染后LRRK2结合NLRC4。同时，结构分析发现LRRK2通过其WD40结构域和NLRC4的LRR结构域结合。另外，LRRK2促进NLRC4 Ser533磷酸化进而参与NLRC4炎症小体组装过程。体内实验结果发现S. Typhimurium感染后LRRK2敲除小鼠中IL-1β产生显著减少，并导致各脏器中细菌含量增加和更高的致死率。因此，本课题研究发现了LRRK2通过促进NLRC4炎症小体参与机体抵抗感染的新机制。论文发表在Journal of Experimental Medicine。..c. 揭示NG2+胶质细胞在不同类型EAE中的作用异同： NG2+胶质细胞在实验性自身免疫性脑脊髓炎（EAE）中的作用机制还不清楚。我们应用PDGFRα-CreER特异地诱导白喉毒素（DTA）在NG2+胶质细胞中表达，成功地在小鼠中枢神经系统（CNS）中部分剔除NG2+胶质细胞。我们发现CNS中部分剔除NG2+胶质细胞的小鼠在诱导Active-EAE和Th1-EAE的发病过程中，表现为临床症状减轻、髓鞘蛋白脱落减少以及炎症细胞浸润减少，说明NG2+胶质细胞能够增强胶质细胞以减轻Active-EAE和Th1-EAE的发病程度。与此相反，在Th17-EAE小鼠中，NG2+胶质细胞能够抑制EAE地发生。我们的结果提示NG2+胶质细胞在不同诱导方式EAE发生中的作用是不同的，因此在治疗方法上也应该有差异的。