Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Cell Cycle Checkpoints
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Cell Proliferation
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Cells, Cultured
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Cellular Senescence*
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Coumarins / pharmacology
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Cytoplasmic Granules / immunology*
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Enzyme Inhibitors / pharmacology
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Exocytosis*
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Extracellular Matrix Proteins / metabolism
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Hepatic Stellate Cells / metabolism
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Humans
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Immunologic Surveillance*
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Isocoumarins
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Liver / metabolism
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Liver Cirrhosis / immunology
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Macrolides / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Perforin / genetics
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RNA Interference
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RNA, Small Interfering
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Serine Proteinase Inhibitors / pharmacology
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Tumor Necrosis Factor Decoy Receptors
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beta-Galactosidase / metabolism
Substances
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Coumarins
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Enzyme Inhibitors
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Extracellular Matrix Proteins
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Isocoumarins
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Macrolides
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RNA, Small Interfering
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Serine Proteinase Inhibitors
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TNFRSF10D protein, human
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Tumor Necrosis Factor Decoy Receptors
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Perforin
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3,4-dichloroisocoumarin
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concanamycin A
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beta-Galactosidase