Granule exocytosis mediates immune surveillance of senescent cells

• Published in: Oncogene Vol. 32; no. 15; pp. 1971 - 1977
• Main Authors: Sagiv, A, Biran, A, Yon, M, Simon, J, Lowe, S W, Krizhanovsky, V
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.04.2013; Nature Publishing Group
• Subjects: 631/250/1619/382; 631/67/580/1884; 631/80/313/1481; 631/80/509; Animals; Apoptosis; Apoptosis - drug effects; beta-Galactosidase - metabolism; Casualties; Cell Biology; Cell Cycle Checkpoints; Cell Proliferation; Cells; Cells, Cultured; Cellular Senescence; Coumarins - pharmacology; Cytoplasmic Granules - immunology; Enzyme Inhibitors - pharmacology; Exocytosis; Extracellular Matrix Proteins - metabolism; Genetic aspects; Hepatic Stellate Cells - metabolism; Human Genetics; Humans; Immunologic Surveillance; Internal Medicine; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Liver; Liver - metabolism; Liver Cirrhosis - immunology; Liver diseases; Macrolides - pharmacology; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Knockout; Oncology; Original; original-article; Perforin - genetics; Physiological aspects; RNA Interference; RNA, Small Interfering; Rodents; Serine Proteinase Inhibitors - pharmacology; Tumor Necrosis Factor Decoy Receptors; Tumors; Israel; perforin; liver fibrosis; cellular senescence
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.206

Senescence is a stable cell cycle arrest program that contributes to tumor suppression, organismal aging and certain wound healing responses. During liver fibrosis, for example, hepatic stellate cells initially proliferate and secrete extracellular matrix components that produce fibrosis; however, these cells eventually senesce 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. 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.