IL-10-induced senescence of HSCs enhances the activation and cytotoxicity of NK cells via NKG2D pathway to attenuate liver fibrosis in vivo and vitro

Liver fibrosis, characterized by excessive extracellular matrix (ECM) deposition, can progress to cirrhosis and hepatocellular carcinoma. Hepatic stellate cells (HSC) drive fibrogenesis through collagen accumulation. While natural killer (NK) cells are known to mediate the antifibrotic effects of interleukin-10 (IL-10), the underlying mechanisms remain elusive. Here, we demonstrate that IL-10 enhances NK cell activation and cytotoxicity by inducing HSC senescence. In vitro and in vivo experiments showed that IL-10-induced HSC senescence upregulates NK cell-activating ligands (MICA/B, ULBP2, and PVR in humans; RAE-1 in mice), which in turn promotes the expression of NK cell-activating receptors (NKG2D and NKP46) and co-activating receptors (CD226), enhancing NK cell cytotoxicity. Blocking NKG2D attenuated the immune-enhancing effects of IL-10-induced senescent HSC on NK cells. Moreover, IL-10-induced senescent HSC secrete CCL5, recruiting NK cells to fibrotic livers and suppressing fibrosis progression. Collectively, our findings reveal that IL-10 attenuates liver fibrosis by inducing HSC senescence, which enhances NK cell activation and cytotoxicity via the NKG2D pathway.