原发性硬化性胆管炎(PSC)的进展与炎症密切相关，具体机制尚不明。我们发现，小鼠PSC模型中，肝脏III类固有淋巴细胞(ILC3)数量升高、炎症因子IL-22释放增加；整体敲除β6基因，可减少ILC3数目和IL-22释放，缓解肝脏纤维化。提取肝脏ILC3，发现ILC3表达TGFβ1受体；阻断该受体可抑制ILC3增殖活化，以及ILC3增殖活化的调控因子c-Kit表达下降。提示αvβ6能通过TGFβ1-c-Kit促进ILC3增殖活化，导致纤维化。本项目拟使用β6基因敲除小鼠等模型，证实ILC3激活在PSC中的作用；提取β6+/+/β6-/- ILC3，抑制/上调αvβ6-TGFβ1通路，观察ILC3增殖和活化的情况；分子水平探讨αvβ6-TGFβ1-c-Kit通路促进ILC3增殖活化的机制。前瞻性探讨肝脏αvβ6和ILC3的表达与PSC患者的临床关系。本研究将为开发PSC干预靶点提供科学依据。

Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease of unknown etiology, characterized by inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts, which ultimately progresses to biliary cirrhosis. Our published work demonstrated that integrin αvβ6 plays a critical important role in regulation of biliary inflammation and liver fibrosis when PSC occurs. However, the mechanism that how αvβ6 works on regulation of biliary inflammation is still unknown. Our previous data showed that in a PSC model, the number of group 3 innate lymphoid cell (ILC3), secretion of interleukin 22 (IL-22) increased and had a positive relationship with αvβ6 increasing. Furthermore, knockdown of β6, blockade of αvβ6 and TGFβ1 can decrease the number of ILC3 and secretion of IL-22. We isolated ILC3 cells from β6+/+和β6-/- mice, treated them by TGFβ1 receptor antibody. We found that ILC3 activation was inhibited, and expression of c-Kit (one of the key regulator factors of ILC3’s proliferation and activation) were increased.. These results reveal that αvβ6 can promote ILC3’s proliferation and activation by TGFβ1-Smad2-c-Kit, and then induces biliary inflammation. We are going to do further in vivo and in vitro experiments to investigate which subgroup of ILC3 works in PSC and how does this subgroup of ILC3 work. We also try to figure out the role of αvβ6 in regulation of ILC3 pathway and how does this regulation work in PSC development. Finally, we will do experiments to confirm the relationships between αvβ6, ILC3 and clinical or pathological features of PSC by using liver samples from PSC patients. Our study will give a new scientific sight and new target sites for prevention and treatment of PSC.