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      STING: infection, inflammation and cancer

      review-article
      Nature Reviews. Immunology
      Nature Publishing Group UK
      Innate immunity, Infection, Inflammatory diseases, Cytokines

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          Key Points

          • Stimulator of interferon genes (STING) is activated by binding to cyclic dinucleotides (CDNs), which results in potent cytokine production. CDNs are produced by certain intracellular bacteria and are generated by the cyclic GMP–AMP synthase (cGAS) following binding to cytosolic DNA species, such as viral DNA.

          • STING-inducible innate immune molecules are essential for protection of the host against pathogens and are important for the stimulation of adaptive immunity.

          • Self-DNA, for example from the nucleus or mitochondria, can leak into the cytosolic compartment and stimulate STING activity to cause autoinflammatory disease. Certain mutations in the gene encoding STING can cause the protein to become permanently active and similarly induce autoinflammatory responses.

          • STING can be activated in phagocytes by DNA released from engulfed tumour cells and drive the production of cytokines necessary for generating robust antitumour T cell responses.

          • DNA-damaging agents can cause the release of nuclear DNA into the cytosol that stimulates STING-dependent cytokine production and phagocyte infiltration. This may be essential for eliminating damaged cells and generating antitumour T cell responses, but chronic stimulation may also promote inflammation-aggravated cancer.

          • STING agonists exert potent antitumour activity and may be effective, novel adjuvants in vaccine formulations. In contrast, inhibitors of STING signalling may be beneficial for the treatment of autoinflammatory disease, such as systemic lupus erythematosus (SLE), Aicardi–Goutières syndrome (AGS) and STING-associated vasculopathy with onset in infancy (SAVI).

          Supplementary information

          The online version of this article (doi:10.1038/nri3921) contains supplementary material, which is available to authorized users.

          Abstract

          Activation of STING (stimulator of interferon genes) by cytosolic aberrant DNA species or cyclic dinucleotides triggers transcription of numerous innate immune genes. In this Review, the author summarizes recent insights into the regulation of STING signalling and its role in autoinflammatory disease and cancer.

          Supplementary information

          The online version of this article (doi:10.1038/nri3921) contains supplementary material, which is available to authorized users.

          Abstract

          The rapid detection of microbial agents is essential for the effective initiation of host defence mechanisms against infection. Understanding how cells detect cytosolic DNA to trigger innate immune gene transcription has important implications — not only for comprehending the immune response to pathogens but also for elucidating the causes of autoinflammatory disease involving the sensing of self-DNA and the generation of effective antitumour adaptive immunity. The discovery of the STING (stimulator of interferon genes)-controlled innate immune pathway, which mediates cytosolic DNA-induced signalling events, has recently provided important insights into these processes, opening the way for the development of novel immunization regimes, as well as therapies to treat autoinflammatory disease and cancer.

          Supplementary information

          The online version of this article (doi:10.1038/nri3921) contains supplementary material, which is available to authorized users.

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          Most cited references56

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          STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors.

          Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8(+) T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-? production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-? production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway.

            Eukaryotic cells sterilize the cytosol by using autophagy to route invading bacterial pathogens to the lysosome. During macrophage infection with Mycobacterium tuberculosis, a vacuolar pathogen, exogenous induction of autophagy can limit replication, but the mechanism of autophagy targeting and its role in natural infection remain unclear. Here we show that phagosomal permeabilization mediated by the bacterial ESX-1 secretion system allows cytosolic components of the ubiquitin-mediated autophagy pathway access to phagosomal M. tuberculosis. Recognition of extracelluar bacterial DNA by the STING-dependent cytosolic pathway is required for marking bacteria with ubiquitin, and delivery of bacilli to autophagosomes requires the ubiquitin-autophagy receptors p62 and NDP52 and the DNA-responsive kinase TBK1. Remarkably, mice with monocytes incapable of delivering bacilli to the autophagy pathway are extremely susceptible to infection. Our results reveal an unexpected link between DNA sensing, innate immunity, and autophagy and indicate a major role for this autophagy pathway in resistance to M. tuberculosis infection. Copyright © 2012 Elsevier Inc. All rights reserved.
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              DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity.

              Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.
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                Author and article information

                Contributors
                gbarber@med.miami.edu
                Journal
                Nat Rev Immunol
                Nat. Rev. Immunol
                Nature Reviews. Immunology
                Nature Publishing Group UK (London )
                1474-1733
                1474-1741
                25 November 2015
                2015
                : 15
                : 12
                : 760-770
                Affiliations
                GRID grid.26790.3a, ISNI 0000 0004 1936 8606, Department of Cell Biology and Sylvester Comprehensive Cancer Center, , University of Miami School of Medicine, ; Miami, 33136 Florida USA
                Article
                BFnri3921
                10.1038/nri3921
                5004891
                26603901
                104a205c-b9ca-4b89-a74e-ee07b68ecd05
                © Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2015

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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                © Springer Nature Limited 2015

                innate immunity,infection,inflammatory diseases,cytokines

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