Cytoplasmic chromatin triggers inflammation in senescence and cancer

Abstract

Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing1–3. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence4,5, a form of terminal cell cycle arrest associated with pro-inflammatory responses6. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA sensing cGAS-STING pathway, leading to both short-term inflammation to restrain activated oncogene and chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype (SASP) in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.

STING SNP R293Q Is Associated with a Decreased Risk of Aging-Related Diseases

“…A highly sensitive immune system is per se of advantage; however, in later life when several aging mechanisms may result in increased cell death due to telomere shortening, oxidative stress or accumulation of mutations resulting in increased release of DAMPs, it may drive the process of inflamm-aging. Our data fit well recent studies showing innate immune sensing via the cGAS-STING pathway to drive senescence by regulating SASP factors [25, 26]. However, aging is a multifactorial process, as reviewed by López-Otín et al [40].…”

“…Furthermore, it has recently been found that innate immune signaling via cGAS also promotes senescence through the secretion of inflammatory cytokines and chemokines and by involving auto- and paracrine signaling. In addition, cGAS as well as STING knockout mice exhibit a reduced SASP upon irradiation compared to wild-type mice [25, 26]. …”

Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

“…We thus infected the reconstituted MEFs with herpes simplex virus 1 (HSV-1, a DNA virus) or vesicular stomatitis virus (VSV, an RNA virus) and indeed noted that cells expressing the STING variants were resistant to viral replication (Figure 2F). Of interest is that it has recently been reported that the STING pathway can influence cellular senescence, a cell-autonomous growth arrest program, by inducing senescence-associated secretory phenotype (SASP) factors such as IL-6 (Dou et al, 2017; Gl€uck et al, 2017; Yanget al, 2017). Because we had observed that STING (R284S) can induce IL-6, we evaluated whether this variant can influence SASP (Figure 2D).…”

Chromosomal instability drives metastasis through a cytosolic DNA response

“…The repercussions of STING activation are context-dependent and range from senescence to tumorigenesis 21,27,28,30 . Given that chromosomally unstable cells are awash with cytosolic DNA, we raise the interesting possibility that by suppressing downstream type I interferon signaling 30 and instead upregulating the alternative NF-κB pathway, they have substituted a lethal epithelial response to inflammation with that of myeloid-derived cells 36,37 , thereby engaging in some form of immune mimicry. Restoring normal responses to inflammation would constitute a viable therapeutic strategy to target chromosomally unstable cells.…”