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The Role of IL-17 Imbalance in Promoting the Pyroptosis in ImmuneMediated Liver Injury through STAT3-IFI16 Axis

Wenfang Xu, Yanan Wang, Changzhong Jin, Weiyang Zhang, Jiangnan Chen, Xuefang Chen, Junli Gao, Junshun Gao, Hong Wang

Autoimmune Hepatitis (AIH), characterized with excessive production of proinflammatory cytokines and progressive damage of hepatocytes, is an inflammatory disease of unclear pathogenesis. AIH affects all age group and occurs mainly in women. Pyroptosis is a novel programmed cell death featured with a distinct morphology associated with cell bursting and release of proinflammatory cytokines. A deeper understanding of the pathogenesis of AIH and its related pyroptosis will contribute to the development of novel therapy for AIH patients. We aimed to investigate the role of Interleukin 17 (IL-17) in immune-mediated liver injury caused by Concanavalin A-induced AIH based on integrated study using primary mouse hepatocytes and BALB/c mouse model. The levels of cytokines were measured by ELISA, and RT-qPCR was conducted to detect the mRNA expression of STAT3 and IFI16. The protein expression of STAT3 and IFI16 was measured by western blotting. Immunohistochemical staining and transmission electron microscopy were applied to evaluate the liver histopathological changes of the mice under different treatments. The primary mouse hepatocytes modeling demonstrated that the levels of IFI16, IL-1b, IL-18, LDH and STAT3 were significantly increased in hepatocytes treated with IL-17, and further elevated followed by STAT3-Overexpressed (STAT3-OE) lentivirus treatment relative to the controls (p<0.01). Importantly, cell pyroptosis was observed in hepatocytes treated with IL-17, and severe cell damage was observed after STAT3-OE lentivirus treatment. In addition, a binding interaction between IFI16 and STAT3 was detected in IL-17 treated hepatocytes. In the BALB/c mouse modeling, glutathione transaminase activity was enhanced in ConA-induced AIH mice compared to that in control group (p<0.01). Aggravated liver damage in mice treated with STAT3-OE lentivirus was observed. However, liver damage was alleviated in mice treated with anti-IL-17 neutralizing antibody or STAT3-knockdown lentivirus. Hence, IL-17 plays an important role in activating STAT3 and up-regulating IFI16, which may promote the pyroptosis in the progression of AIH-related liver injury through STAT3-IFI16 axis. Therapeutic potential of targeting IL-17-STAT3-IFI16 pathway for AIH patients deserve to be further investigated.