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 Propionibacterium acnes/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.
[1]Soochow Univ, Key Lab Stem Cells & Med Biomat Jiangsu Prov, State Key Lab Radiat Med & Protect, Affiliated Hosp 1,Inst Translat Med,Med Coll, Suzhou, Peoples R China;
[2]Univ Chinese Acad Sci, Chinese Acad Sci, CAS Key Lab Tissue Microenvironm & Tumor, Shanghai Inst Nutr & Hlth,Shanghai Inst Biol Sci, Shanghai, Peoples R China;
[3]Fudan Univ, Dept Med Oncol, Shanghai Canc Ctr, Shanghai, Peoples R China
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