The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Soochow University, Suzhou, China.
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Front Immunol. 2019 Aug 20;10:1980. doi: 10.3389/fimmu.2019.01980. eCollection 2019.
Myeloid derived suppressor cells (MDSC) in the liver microenvironment protects against the inflammation-induced liver injury in fulminant hepatitis (FH). However, the molecular mechanism through which MDSC is recruited into the inflamed liver remain elusive. Here we identified a protein kinase Tpl2 as a critical mediator of MDSC recruitment into liver during the pathogenesis of /LPS-induced FH. Loss of Tpl2 dramatically suppressed MDSC mobilization into liver, leading to exaggerated local inflammation and increased FH-induced mortality. Mechanistically, although the protective effect of Tpl2 for FH-induced mortality was dependent on the presence of MDSC, Tpl2 neither directly targeted myeloid cells nor T cells to regulate FH pathogenesis, but functioned in hepatocytes to mediate the induction of MDSC-attracting chemokine CXCL1 and CXCL2 through modulating IL-25 (also known as IL-17E) signaling. As a consequence, increased MDSC in the inflamed liver specifically restrained the local proliferation of infiltrated pathogenic CD4 T cells, and thus protected against the inflammation-induced acute liver failure. Together, our findings established Tpl2 as a critical mediator of MDSC recruitment and highlighted the therapeutic potential of Tpl2 for the treatment of FH.
髓源抑制细胞（MDSC）在肝脏微环境中可防止暴发性肝炎（FH）中炎症诱导的肝损伤。然而，MDSC 招募到炎症肝脏的分子机制仍不清楚。在这里，我们鉴定出蛋白激酶 Tpl2 是 LPS 诱导的 FH 发病过程中 MDSC 招募到肝脏的关键介质。Tpl2 缺失可显著抑制 MDSC 向肝脏的迁移，导致局部炎症加重和 FH 诱导的死亡率增加。在机制上，尽管 Tpl2 对 FH 诱导的死亡率的保护作用依赖于 MDSC 的存在，但 Tpl2 既不直接靶向髓样细胞，也不靶向 T 细胞来调节 FH 的发病机制，而是在肝细胞中通过调节白细胞介素 25（也称为白细胞介素 17E）信号来介导 MDSC 趋化因子 CXCL1 和 CXCL2 的诱导。因此，在炎症肝脏中增加的 MDSC 特异性抑制浸润的致病性 CD4 T 细胞的局部增殖，从而防止炎症诱导的急性肝衰竭。总之，我们的研究结果确立了 Tpl2 作为 MDSC 招募的关键介质，并强调了 Tpl2 治疗 FH 的治疗潜力。
