SR-A/IRF5信号轴调控巨噬细胞极化在日本血吸虫肝病中的作用及机制

Schistosomiasis is one of the most serious parasitic diseases in China and the world. The most serious immunopathology is the egg-induced granulomatous inflammatory response and fibrosis in the liver, which impacts on the hosts’ living quality, or even mortality. Studies have shown that macrophage polarization plays important roles in the development of liver immunopathology, but its specific mechanism has not been elucidated. Our preliminary work suggested that the high expression of SR-A in macrophages from Schistosoma japonicum infected mice is involved in macrophage polarization and the development of hepatic fibrosis. It had been suggested that IRF5 is essential in the regulation of macrophage polarization. Therefore, our subject intends to prove the following scientific assumptions by in vivo and in vitro experiments: SR-A promotes M2 polarization by inhibiting the expression and activation of IRF5, and then facilitates the development of liver fibrosis. Therefore, the aim of this study is to investigate the mechanism of SR-A/IRF5 axis in regulating macrophage polarization and the pathogenesis of liver fibrosis, and provides experimental and theoretical basis for the prevention and treatment of hepatic fibrosis of clinical schistosomiasis.

血吸虫病是当前我国乃至世界最严重的寄生虫病之一。血吸虫感染造成的核心损害是由肝脏内的虫卵引起肉芽肿以及继发的肝纤维化，最终导致肝硬化、门脉高压症等，甚至危及患者生命。研究表明巨噬细胞极化在血吸虫肝脏免疫病理形成过程中发挥重要的功能，然而其具体机制尚未阐明。我们的前期工作表明，血吸虫感染宿主体内巨噬细胞中高表达的清道夫受体A（SR-A）参与巨噬细胞极化及肝纤维化的进展。又有文献提示干扰素调节子IRF5在巨噬细胞极化的调控中至关重要。因此，本课题拟通过采用体内外实验来证明如下的科学假设：SR-A通过抑制IRF5的表达及激活来促进巨噬细胞向M2极化，从而参与血吸虫病肝纤维化的发生发展。本研究从多个层面探讨SR-A—IRF5信号轴参与巨噬细胞极化介导的肝纤维化病理发展的机制，为临床血吸虫病肝纤维化的防治工作提供实验 及理论依据。

血吸虫病是当前我国乃至世界最严重的寄生虫病之一。血吸虫感染造成的核心损害是由肝脏内的虫卵引起肉芽肿以及继发的肝纤维化。研究表明巨噬细胞极化及适应性T细胞在血吸虫肝脏免疫病理形成过程中发挥重要的功能，然而其具体机制未明。通过项目实施，我们主要阐明了以下几个科学问题：（1）血吸虫感染宿主体内巨噬细胞中高表达的SR-A通过抑制IRF5的激活促进M2极化与Th2分化，进而促进肝脏病理的进展。（2）岩藻多糖（Fucoidan）通过诱导CD4+T细胞分化为Treg细胞（而不是Th2细胞），从而参与抑制肝脏病理的形成。（3）代谢因子PPAR-γ以及PAK1可以通过巨噬细胞诱导的Treg细胞，从而参与抑制肝脏免疫病理的形成。（4）血吸虫感染后虫源性抗原能够诱导巨噬细胞的糖脂代谢的重塑。本研究从多个层面多个角度探讨巨噬细胞-CD4+T细胞轴在血吸虫肝病发展的作用机制，为临床血吸虫病肝纤维化的防治工作提供实验及理论依据。