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CHI3L1 protects TAA-induced liver injury via regulating STAT3-mediated T cell differentiation

Jian Gu  Yunjie Lu  Hao Lu  Xuhao Ni  Ling Lu  
【摘要】:Background and aims: Chitinase 3–like 1(CHI3L1) is a prototypic chitinase-like protein that has been retained over species and evolutionary time. The role of CHI3L1 in liver injury and liver failure has not been defined. This study was designed to dissect the functional role and potential mechanism of CHI3L1 in TAA-induced liver injury. Methods: Murine liver injury model was established by injection of TAA. CHI3L1 as well as CHI3L1-ko mice were used to determine the role of CHI3L1 in liver injury. To investigate the mechanism of CHI3L1 in protecting liver injury, the level of STAT3 and IFN-r were measured. Results: The CHI3L1 levels were decreased in patients after liver injury. High levels of CHI3L1 are associated with the improvement of liver function followed by medical treatment. To determine the role and mechanism of CHI3L1 in liver failure, mouse TAA-induced injury model was used. Injection of a recombinant CHI3L1(r CHI3L1) reduced the liver damage and improved liver function. However, knockout of CHI3LI(CHI3LI KO) resulted in exacerbating liver injury, as evidenced by increasing serum ALT and liver damage histologically. Unlike in controls, r CHI3L1 treatment decreased the expression of T-bet, IFN-r, and Th17 but increased Foxp3 regulatory T cells(Foxp3+Tregs). CHI3L1 treatment decreased the phosphorylation of STAT3, while CHI3L1 knockout increased STAT3 phosphorylation. Moreover, administration of recombinant m IFN-r or STAT3 inhibitor increased TAA-induced liver injury, which accompanied by increased Th17 and reduced Foxp3 expression in CHI3LI-deficient mice. Conclusion: This study demonstrates that CHI3 LI protects livers against TAA-induced liver injury. CHI3LI-mediated hepato-protection by inhibiting Th17 and promoting Foxp3+Tregs in a Stat3-dependent manner. Our findings established the regulatory role of CHI3L1 in liver injury, and provides the novel therapeutic targets in in liver injury and liver failure.

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