Senescence is a permanent form of cell cycle arrest that contributes to tumor suppression, organismal aging and certain wound healing responses. For example, during liver fibrosis, hepatic stellate cells (HSCs) initially proliferate and secrete extracellular matrix components that produce the characteristic patterns of fibrosis; however, these cells eventually senescence and are cleared by immune cells, including natural killer (NK) cells. Here, we examine how NK cells target senescent cells and assess the impact of this process on liver fibrosis. Using both pharmacologic and genetic approaches, we show that granule exocytosis, but not death-receptor-mediated apoptosis, is required for NK-cell-mediated killing of senescent cells. This pathway bias is due to upregulation of the decoy death receptor, Dcr2, an established senescence marker that attenuates NK-mediated cell death. Accordingly, mice with defects in granule exocytosis accumulate senescent stellate cells and display more liver fibrosis in response to a fibrogenic agent. Our results thus provide new insights into the immune surveillance of senescent cells and reveal how granule exocytosis has a protective role against liver fibrosis. In principle, similar mechanisms may influence immune surveillance of senescent cells throughout the organism.
