Aggravated liver injury but attenuated inflammation in PTPRO-deficient mice following LPS/D-GaIN induced fulminant hepatitis

Abstract

Background/Aims: Critical roles of PTPRO and TLR4 have been implicated in hepatocellular carcinoma. However, little is known about their modifying effects on inflammation-related diseases in liver, particularly fulminant hepatitis (FH). We aim to investigate the potential role of PTPRO and its interaction with TLR4 in LPS/D-GaIN induced FH. Methods: A LPS/ D-GaIN induced mouse FH model was used. RAW264.7 cells were transfected with PTPRO over-expressed lentiviral plasmids for further investigation. Results: The mortality of PTPRO KO mice is higher than WT mice after LPS/D-GaIN administration. Aggravated liver injury was demonstrated by increased level of serous ALT and AST and numerous hepatic cells death in PTPRO KO mice following LPS/D-GaIN administration. Interestingly, inflammation was attenuated in PTPRO-deficient mice following LPS/D-GaIN administration, which was suggested by decreased inflammatory cytokines (TNF-α, IFN-γ, IL-lβ, IL-6, IL-17A and IL- 12) and cells infiltrating into spleen (CD3 + IFN-γ + cells, CD3 + TNF-α + cells, F4/80 + /TLR4 + cells). A feedback regulation between PTPRO and TLR4 dependent on NF-κB signaling pathway was demonstrated in VIVO and in vitro. Conclusion: PTPRO plays an important role in FH by interacting with TLR4. The crosstalk between PTPRO and TLR4 is a novel bridge linking innate immune and adaptive immune in acute liver injury.