Abstract
Cellular senescence is a stress response mechanism that limits tumorigenesis and tissue damage. Induction of cellular senescence commonly coincides with an immunogenic phenotype that promotes self-elimination by components of the immune system, thereby facilitating tumor suppression and limiting excess fibrosis during wound repair. The mechanisms by which senescent cells regulate their immune surveillance are not completely understood. Here we show that ligands of an activating Natural Killer (NK) cell receptor (NKG2D), MICA and ULBP2 are consistently up-regulated following induction of replicative senescence, oncogene-induced senescence and DNA damage - induced senescence. MICA and ULBP2 proteins are necessary for efficient NK-mediated cytotoxicity towards senescent fibroblasts. The mechanisms regulating the initial expression of NKG2D ligands in senescent cells are dependent on a DNA damage response, whilst continuous expression of these ligands is regulated by the ERK signaling pathway. In liver fibrosis, the accumulation of senescent activated stellate cells is increased in mice lacking NKG2D receptor leading to increased fibrosis. Overall, our results provide new insights into the mechanisms regulating the expression of immune ligands in senescent cells and reveal the importance of NKG2D receptor-ligand interaction in protecting against liver fibrosis.
Highlights
Once thought of as passive state of cell cycle arrest, senescent cells are known to govern physiological processes such as tumor prevention and tissue repair [1,2,3,4,5]
The NKG2D ligands MICA, ULBP1 and ULBP2 were consistently upregulated at www.impactaging.com least two-fold in all three types of senescent IMR-90 fibroblasts compared to growing control cells (p
In this study we investigated the mechanisms which control the recognition of senescent cells by Natural Killer (NK) cells
Summary
Once thought of as passive state of cell cycle arrest, senescent cells are known to govern physiological processes such as tumor prevention and tissue repair [1,2,3,4,5]. The senescent state can be induced in response to various stressors leading to irreversible cell cycle arrest, and often the development of an altered secretome. Such stressors include telomere dysfunction, oncogene activation, direct DNA damage, elevated intracellular reactive oxygen species (ROS) and cell-cell fusion [1,2,3, 6]. Induction of senescence regulated by multiple signaling pathways performs essential physiological functions by limiting tumorigenesis and tissue damage
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