The list of sequences of primers in this study.

Schistosomiasis is characterized by egg-induced hepatic granulomas and subsequent fibrosis. Monocyte-derived macrophages play critical and plastic roles in the progression and regression of liver fibrosis, adopting different polarization phenotypes. Mammalian STE20-like protein kinase 1 (MST1), a serine/threonine kinase, has been established to act as a negative regulator of macrophage-associated inflammation. However, the specific role of MST1 in Schistosoma-induced liver fibrosis has not been fully understood. In this study, we demonstrate that macrophage MST1 functions as an inhibitor of inflammation and fibrosis following infection with Schistosoma japonicum (S. japonicum). Mice with macrophages-specific Mst1 knockout (termed Mst1△M/△M) mice developed exacerbated liver pathology, characterized by larger egg-induced granulomas, and increased fibrosis post infection. This was accompanied by enhanced production of proinflammatory cytokines (IL1B, IL6, IL23, TNFA and TGFB) and a shift in macrophage phenotype towards Ly6Chigh. Mechanistically, MST1 activation by soluble egg antigen (SEA) promoted PPARγ-mediated CD36 expression, enhancing phagocytosis and consequently upregulation of fibrolytic genes such as Arg1 and Mmps. Conversely, MST1 deletion leads to up-regulation of pro-inflammatory genes instead of fibrolytic genes in macrophages, accompanied by decreased expression of CD36 and impaired phagocytosis. Furthermore, the ablation of MST1 enhances NF-κB activation in S. japonicum-infected and SEA-stimulated macrophages, resulting in increased production of proinflammatory cytokines. Overall, our data identified MST1 as a novel regulator for egg-induced liver fibrosis via modulation of macrophage function and phenotype by CD36-mediated phagocytosis and suppression of NF-κB pathway.

血吸虫病以虫卵诱导的肝肉芽肿及继发性纤维化为核心病理特征。单核细胞源性巨噬细胞在肝纤维化的进展与消退过程中发挥关键且具有可塑性的作用，可呈现多种不同的极化表型。哺乳动物STE20样蛋白激酶1（MST1）作为一种丝氨酸/苏氨酸激酶，已被证实为巨噬细胞相关炎症的负调控因子。然而，MST1在血吸虫诱导的肝纤维化中的具体作用尚未完全明确。本研究证实，在日本血吸虫（S. japonicum）感染后，巨噬细胞MST1可作为炎症与纤维化的抑制因子。巨噬细胞特异性敲除Mst1的小鼠（命名为Mst1△M/△M小鼠）感染后出现更为严重的肝脏病理损伤，表现为虫卵诱导的肉芽肿体积更大、纤维化程度显著升高。该现象伴随促炎细胞因子（IL1B、IL6、IL23、TNFA及TGFB）的生成增多，以及巨噬细胞表型向Ly6C高表达亚型的偏移。机制研究显示，可溶性虫卵抗原（SEA）可激活MST1，进而促进过氧化物酶体增殖物激活受体γ（PPARγ）介导的CD36表达，增强巨噬细胞吞噬功能，最终上调精氨酸酶1（Arg1）、基质金属蛋白酶（Mmps）等纤维溶解相关基因的转录。反之，MST1缺失会使巨噬细胞中转录上调促炎基因而非纤维溶解基因，同时伴随CD36表达降低与吞噬功能受损。此外，在日本血吸虫感染及SEA刺激的巨噬细胞中，MST1的敲除会增强核因子κB（NF-κB）的激活，进而促进促炎细胞因子的生成。综上，本研究数据表明，MST1可通过CD36介导的吞噬作用及对NF-κB通路的抑制，调控巨噬细胞功能与表型，从而成为虫卵诱导肝纤维化的新型调控因子。