IL-21 attenuates liver inflammation by enhancing myeloid-derived suppressor cells immunosuppressive function in chronic HBV infection

BACKGROUND: Chronic hepatitis B virus (HBV) infection progression is closely associated with repeated inflammatory liver injury. Myeloid-derived suppressor cells (MDSCs), known to suppress inflammatory responses during hepatitis, may play a protective role in mitigating liver damage; nevertheless, the precise functional specialization of MDSC subpopulations and the critical regulator in controlling their suppressive capacity remain incompletely understood. This study investigates the immunoregulatory role of IL-21, a pleiotropic immunomodulatory cytokine, in modulating MDSC function and its implications for HBV-associated liver inflammation prognosis. METHODS: The frequencies of peripheral and intrahepatic MDSCs, along with serum IL-21 levels, in patients with chronic HBV infection were measured with freshly isolated samples. C57BL/6 mice carrying pAAV-HBV1.2 plasmids was established to explore the effect of IL-21 on aminotransferase levels and MDSC function. RESULTS: Patients with chronic HBV infection demonstrated significantly elevated frequencies of circulating MDSCs compared to healthy controls. Of note, the granulocytic MDSCs (gMDSCs) were markedly more abundant in hepatic tissues than in peripheral blood. Strikingly, a significant inverse correlation was observed between circulating gMDSC frequencies and serum ALT levels specifically in patients with elevated serum IL-21 concentrations, whereas this correlation was absent in the low IL-21 subgroup. In vitro functional assays demonstrated that exogenous IL-21 potentiated the immunosuppressive capacity of MDSCs, significantly attenuating IFN-γ production in co-cultured T cells. Consistent with these findings, hydrodynamic injection of IL-21 plasmid in an HBV mouse model resulted in significantly reduced serum ALT levels concomitant with enhanced arginase I expression in hepatic MDSCs. CONCLUSIONS: These results reveal that IL-21 enhances MDSC-mediated immunosuppression, implicating this regulatory axis in the attenuation of hepatic inflammation during chronic HBV infection. These findings provide a novel perspective on the involvement of IL-21 in the negative regulation of intrahepatic inflammation and provide a novel perspective on the role of IL-21 in developing immunotherapeutic strategies to optimize available anti-inflammatory treatments in chronic HBV infection.