Cellular senescence marked with persistent cell cycle arrest plays critical roles in orchestrating tissue remodeling and immune surveillance in response to multiple developmental and physiological stimuli. However, chronic or persistent cellular senescence can promote aberrant inflammatory responses, therefore is linked with variable pathogeneses such as fibrosis, cancer, autoimmune diseases, cardiovascular disease and neurodegenerative disease . Identifying how the immune system detects and responds to senescence signals is critical for our better understanding of the interplay between senescence progression and inflammation, and the pathogenesis of age-related diseases . Triggered by multiple genomic or epigenomic changes, senescent cells undergo characteristic changes including an arrested cell cycle, gene expression alterations, formation of cytoplasmic chromatin fragments (CCFs) [2,3] and the senescence-associated secretory phenotype (SASP) . The SASP includes the secretion of inflammatory cytokines, chemokines and growth factors, mainly regulated by the transcription factor nuclear factor-κB (NF-κB). SASP has been considered as a critical event that triggers immune cell-mediated elimination of senescent cells in the short-term, as well as causing harmful inflammatory responses in the long-term . However, the precise mechanism driving senescence-associated inflammation and its physiological and pathological relevance needs to be uncovered. The immune system relies on pattern recognition receptors to detect various pathogenic components in response to microbial infection. Pathogenic DNA delivered into the cytoplasm is recognized by cytosolic DNA sensors such as cyclic GMP-AMP (cGAMP) synthase (cGAS), interferon-γ-inducible protein16 (IFI16), absent in melanoma 2 (AIM2) and so on, which is a critical mechanism for the detection of pathogens and the induction of innate immune responses . For example, upon detection of pathogenic dsDNA, cGAS triggers the stimulator of interferon genes (STING)-TANK-binding kinase 1 kinase-dependent pathway to activate NF-κB and IFN regulatory factor 3, resulting in the production of inflammatory cytokines and type I interferons, respectively . Additionally, cytosolic self-derived damaged DNA can be detected by cGAS, and induces the production of type I IFN and inflammatory factors [8,9]. Whether dsDNA-containing CCFs in cellular senescence are recognized by cytosolic DNA sensors is largely unknown. Recently, three groups independently reported the biological function of CCFs in triggering inflammation in cellular senescence [10–12]. In recent research by Dou et al., which was published in Nature, the authors report that cGAS aggregates in CCFs in senescent cells, which in turn activates cGAS and its downstream adaptor STING, resulting in the production of SASP. Interestingly, cGAS activation triggered by CCFs does not lead to type I IFN expression, which is likely due to inhibition by p38 MAPK kinase  (Fig. 1). Therefore, CCFs in senescent cells trigger the secretion of SASP program and inflammatory responses via the cGAS-STING pathway. However, another cytosolic DNA sensor, IFI16, does not influence the production of SASP. Interestingly, another study showed that the cytosolic DNA sensors IFI16 and AIM2 are, respectively, associated with the production of IFN-β and IL-1β during cellular senescence . While IFI16 regulates cellular senescence by promoting the p53 pathway and inhibiting telomerase activity, AIM2 might serve as a negative regulator of IFI16 in cellular senescence [13,14]. Until now, there has been no direct evidence showing that CCFs can be recognized by IFI16 and AIM2. However, an important finding is that AIM2 can sense radiation-induced DNA damage, resulting in cell death . Thus, it will be intriguing to further investigate whether CCFs can be detected by other cytosolic DNA sensors, such as IFI16 and AIM2, and the related physiological or pathological consequences. In Dou et al.’s research, the essential role of the cGAS-STING pathway in linking senescence and inflammation is further illustrated by using two mouse models of senescence (ionizing irradiation-induced senescence and oncogene (NRasG12V)-induced senescence, OIS) in vivo. In both models, the STING-null mice showed a sharp decrease in inflammatory gene expression in hepatocytes and less immune cell infiltration compared to wild-type (WT) mice. In the OIS mice model, while the expression of oncogene NRasG12V decreased to a low level at day 12 in WT mice, it remained stable in STING-null mice, ultimately leading to the development of liver tumors. These data reveal that STING is critical for senescence-associated inflammation and immune surveillance in vivo  (Fig. 1). The biological functions of the cGAS-STING pathway in senescence could be further illustrated by investigations using cGAS-null mice, and it will be intriguing to clarify the mechanism by which Ras expression is regulated by STING. Figure 1. View largeDownload slide The cGAS-STING pathway triggers inflammation in senescence and cancer. Senescent cells induced by oncogene activation, DNA damage or replicative limit release chromatin fragments into the cytoplasm to form CCFs. The cytosolic DNA sensor cGAS senses the CCFs, leading to activation of the cGAS-STING pathway to promote SASP secretion. Short-term inflammation mediated by SASP is essential for the recruitment of immune cells for immune surveillance, while long-term inflammation is associated with senescence evasion and cancer progression. CCFs, cytoplasmic chromatin fragments. SASP, senescence-associated secretion phenotype. Figure 1. View largeDownload slide The cGAS-STING pathway triggers inflammation in senescence and cancer. Senescent cells induced by oncogene activation, DNA damage or replicative limit release chromatin fragments into the cytoplasm to form CCFs. The cytosolic DNA sensor cGAS senses the CCFs, leading to activation of the cGAS-STING pathway to promote SASP secretion. Short-term inflammation mediated by SASP is essential for the recruitment of immune cells for immune surveillance, while long-term inflammation is associated with senescence evasion and cancer progression. CCFs, cytoplasmic chromatin fragments. SASP, senescence-associated secretion phenotype. Whereas senescence potently counteracts tumorigenesis, persistent inflammation may result in tissue damage and even lead to cancer progression. This raises the following question: what is the role of the cGAS-STING pathway in senescence evasion and cancer? Dou et al. immortalized NRasG12V-induced senescent IMR90 cells (termed OIS-evaded) and discovered that the cGAS-STING axis is activated by the CCFs of OIS-evaded cells and promotes the SASP program. Consistent with these observations, cytoplasmic chromatin formed and co-localized with cGAS in multiple breast cell lines. Concomitantly, the expression of inflammatory genes depended on the cGAS-STING pathway and was highly associated with cytoplasmic chromatin formation. Collectively, the CCF-cGAS-STING pathway mediates pro-inflammatory responses in long-term inflammation and senescence evasion in cancer progression (Fig. 1). Whether CCF-triggered SASP can functionally affect the initiation or development of cancer, and how the cGAS-STING pathway integrates with other cellular signaling pathways to regulate immune surveillance and tumorigenesis, remain to be further investigated. In line with these findings, Yang et al. showed that mouse embryonic fibroblasts (MEFs) from cGAS knockout mice spontaneously become immortalized compared with WT MEFs, which are senescent after serial passages. cGAS assembles in the cytoplasmic chromatin foci and triggers inflammatory gene expression in senescent cells . Interestingly, Yang et al. also found that cGAS translocates into the nucleus and accumulates in chromatin during mitosis, but STING remains in the cytoplasm, thus cGAS may have additional functions that are independent of the STING pathway during the cell cycle . Meanwhile, another study by Glück et al. has demonstrated that CCFs are sensed by cGAS and activate STING, promoting senescence by inducing IL-6 in an autocrine manner and by inducing Cxcl10 expression in a paracrine manner . In contrast to the findings by Dou et al., Glück et al. showed that cGAS activation during cellular senescence induces the production of type I IFN in MEFs . This discrepancy might be due to different cell types having been used in these two studies. Indeed, the expression of cGAS and STING is differentially regulated in different tissues (with relatively higher expression in the liver, small intestine and colon, but relatively lower expression in the brain and kidneys) . Thus, the contribution of the cGAS-STING pathway in SASP production and senescence-associated inflammation may vary in different tissues, and it will be intriguing to identify potential CCF sensors in those tissues with low expression of cGAS and STING, such as the brain and kidneys, and clarify the signaling basis of senescence-associated inflammation in those tissues. In conclusion, these findings have uncovered a new molecular mechanism behind the cellular senescence-dependent regulation of inflammation and cancer, and provide an insightful connection between CCFs derived from genomic instability and the progression of senescence and cancer. While short-term inflammation triggered by the CCF-cGAS-STING pathway is required for immune clearance of senescent cells, chronic inflammation mediated by SASP is destructive, resulting in tissue damage and even tumorigenesis. Several interesting directions are worth studying in the future. Is there any involvement of cytoplasmic RNA in cellular senescence and, if so, what is the role of cytoplasmic RNA sensors? What is the biochemical and structural basis for the detection of CCFs by cGAS? What is the biological relevance of cGAS-STING in age-related diseases, such as atherosclerosis and type 2 diabetes? Understanding these questions will expand our understanding of the interplay between the innate immune system and senescence during physiological and pathological conditions, and give rise to the development of new therapeutic strategies against age-related diseases, cancer and other. FUNDING This work was supported by grants from the National Natural Science Foundation of China (81788104) and the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2016-12M-1-003). Conflict of interest statement. None declared. REFERENCES 1. Campisi J . Annu Rev Physiol. 2013 ; 75 : 685 – 705 . https://doi.org/10.1146/annurev-physiol-030212-183653 CrossRef Search ADS PubMed 2. Dou Z , Xu C , Donahue G et al. Nature 2015 ; 527 : 105 – 9 . https://doi.org/10.1038/nature15548 CrossRef Search ADS PubMed 3. Ivanov A , Pawlikowski J , Manoharan I et al. J Cell Biol 2013 ; 202 : 129 – 43 . https://doi.org/10.1083/jcb.201212110 CrossRef Search ADS PubMed 4. Coppé J , Desprez P , Krtolica A et al. Annu Rev Pathol Mech Dis 2010 ; 5 : 99 – 118 . https://doi.org/10.1146/annurev-pathol-121808-102144 CrossRef Search ADS 5. van Deursen J . Nature 2014 ; 509 : 439 – 46 . https://doi.org/10.1038/nature13193 CrossRef Search ADS PubMed 6. Liu J , Cao X . 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National Science Review – Oxford University Press
Published: Dec 20, 2017
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