AUTHOR=Xu Jing , Pei Siyu , Wang Yan , Liu Junli , Qian Youcun , Huang Mingzhu , Zhang Yanyun , Xiao Yichuan TITLE=Tpl2 Protects Against Fulminant Hepatitis Through Mobilization of Myeloid-Derived Suppressor Cells JOURNAL=Frontiers in Immunology VOLUME=10 YEAR=2019 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01980 DOI=10.3389/fimmu.2019.01980 ISSN=1664-3224 ABSTRACT=

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.