ICOSL/ICOS调控IL-21活化日本血吸虫感染小鼠HSCs介导肝纤维化的分子机制

Granuloma formation and subsequent hepatic fibrosis induced by Schistosoma japonicum is the main reason leading to shistosomiasis, and the activation and proliferation of hepatic stellate cells(HSCs)is the key link leading to the occurrence of liver fibrosis. Based on previous studies, it has been found ICOSL/ICOS signal can mediate T cell subgroups (Th1/Th2/Th17/Tfh) polarization and regulate the disease process of chronic schistosomiasis, In recently,we have found that IL-2R is expressed on HSCs and up-regulation of IL-21 contributing liver fibrosis of chistosomiasis by activating HSCs in Mice. Accordingly, we proposed a hypothesis“It is a new perspective of controling progress of liver fibrosis by Tfh cytokine IL-21 activating HSCs regulated by ICOSL/ICOS signal in schistosomiasis”. In this program, we intend to application specific ICOSL gene knock-out and ICOS transgenic mouse models of disease to test this hypothesis, and investigate that the important scientific idea of the effects of IL-21 on the important signal pathway which the TGF-β1/Smad etc. mediate the activation of HSCs and may be potential new pathway, and further elucidating the molecular mechanisms of hepatic fibrosis in shcistosomiasis, the results of this study will provide a new perspective to prevent and control the liver fibrosis in schistosomiasis.

血吸虫虫卵肉芽肿反应及继发纤维化是导致血吸虫致病的主要原因，而肝星状细胞（HSCs）的活化和增殖是肝纤维化的关键环节。本课组在前期系列研究中证明ICOSL/ICOS信号可介导血吸虫慢性致病期T细胞亚群(Th1/Th2/Th17/Tfh)的极化并调节疾病进程，特别是近期研究发现HSCs表面具有IL-21受体，ICOSL/ICOS信号可介导Tfh细胞因子IL-21上调表达活化HSCs导致肝纤维化。据此，提出“ICOSL/ICOS信号调控Tfh细胞因子IL-21介导HSCs活化可能是控制血吸虫病肝纤维化进程的潜在新途径”的科学假设。本项目拟应用本课题组特定的ICOSL敲基因和ICOS转基因小鼠疾病模型验证该假设，拟探讨IL-21介导HSCs活化与经典信号通路TGF-β1/Smad等的相关性及潜在新的信号通路等重要科学问题，深入阐明血吸虫病肝纤维化的分子机制，为血吸虫病肝纤维化的防治提供新的思路。

血吸虫虫卵肉芽肿反应及继发纤维化是导致血吸虫致病的主要原因，而肝星状细胞（HSCs）的活化和增殖是肝纤维化的关键环节。本项目基于前期研究发现HSCs表面具有IL-21受体，ICOSL/ICOS信号可介导Tfh细胞因子IL-21上调表达活化HSCs导致肝纤维化,据此提出“ICOSL/ICOS信号调控Tfh细胞因子IL-21介导HSCs活化可能是控制血吸虫病肝纤维化进程的潜在新途径”的科学假设。本项目应用本课题组特定的ICOSL敲基因和ICOS转基因小鼠疾病模型验证该假设，经过4年的研究取得以下研究成果：（1）Tfh细胞迁移到生发中心通过分泌效应因子IL-21促进B细胞体液免疫应答，体内IL-21刺激显著增加肝脏虫卵肉芽肿的面积，促进肝脏胶原面积的表达，加重肝纤维化;（2）ICOS/ICOSL信号在日本血吸虫感染的病程中可能通过影响脾Tfh细胞生发中心形成及其效应因子IL-21表达进而影响HSCs促进肝纤维化发展;(3) ICOSL-KO小鼠可影响HSCs的活化相关信号通路相关分子基因的表达，尤其以TGF-β1/Smad、PI-3K/AKT、JAK/STAT信号通路中分子基因下调的最为显著。ICOSL-KO小鼠可能通过下调上述信号通路中分子基因的表达，抑制HSCs的活化，进而减轻肝纤维化的发生与发展；（4）在ICOS-Tg小鼠日本血吸虫疾病模型中ICOSL/ICOS信号上调，HSCs活化增强，肝纤维化程度加重。ICOSL/ICOS的上调，可能通过上调TGF-β1/Smad信号蛋白分子的表达，促进了HSCs的活化，进一步加剧肝纤维化的发生与发展。本研究应用ICOSL-KO和ICOS-Tg小鼠日本血吸虫疾病模型深入阐明了ICOSL/ICOS信号可能通过IL-21和TGF-β1/Smad调控HSCs活化的分子机制，为寻找控制肝纤维化的发生发展提供了新的途径。