CD40L-CD40通路调控巨噬细胞浸润和活化参与胰腺纤维化的机制研究

胰腺纤维化是慢性胰腺炎（CP）的特征性病理变化，胰腺星状细胞（PSC）是关键效应细胞，其活化受Th细胞和巨噬细胞协同调控，并共同构成炎症-纤维化微环境。CD40L-CD40在皮肤、肺及肾脏等器官纤维化过程中发挥重要作用，阻断该信号通路可缓解纤维化。与既往研究结果相反，我们发现CD40基因敲除小鼠胰腺纤维化明显加重，巨噬细胞浸润与M2极化显著增多，Th细胞浸润不变。体外研究表明外源重组sCD40L不影响PSC活化，推测敲除CD40不影响Th细胞，而是通过促进巨噬细胞M2极化间接激活PSC。进一步研究发现这可能与CD40下游TRAF5表达明显降低相关（TRAF2和TRAF6不变）。我们拟进一步结合配体CD40L敲除小鼠、巨噬细胞特异性CD40敲除和TRAF5过表达小鼠以及体外细胞共培养体系，深入研究CD40L-CD40信号调控胰腺纤维化的分子机制，从免疫微环境角度为CP的临床治疗提供新靶点。

Chronic pancreatitis (CP) is pathologically characterized by pancreatic fibrosis. Pancreatic stellate cells (PSC) is the major effector cell in pancreatic fibrogenesis, whose activation is coordinately regulated by Th cells and macrophages. Together they constitute the inflammation-fibrotic microenvironment. CD40L-CD40 plays an important role in the fibrosis process of skin, lung, kidney and other organs and blocking this signaling pathway can alleviate fibrosis. Contrary to previous results, we found pancreatic fibrosis in CD40 knockout mice exacerbated, with macrophage infiltration and M2 polarization, and Th cell infiltration remained unchanged. In vitro studies have shown that exogenous recombinant sCD40L did not affect PSC activation. It is speculated that CD40 knockout does not affect Th cells, but promotes M2 polarization of macrophages which activates PSC indirectly. Further research found that this may be related to a significant decrease in the expression of TRAF5 in the downstream of CD40 (TRAF2 and TRAF6 were unchanged). We intend to use the ligand CD40L knockout mice, macrophage-specific CD40 knockout and TRAF5 overexpression mice, and in vitro cell co-culture systems to further study the molecular mechanism of CD40L-CD40 signaling in the regulation of pancreatic fibrosis, providing a new target for the treatment of CP.