The cGAS‐STING pathway: The role of self‐DNA sensing in inflammatory lung disease

Ma, Ru; Serrano, Tatiana P. Ortiz; Davis, Jennifer; Prigge, Andrew D; Ridge, Karen M.

doi:10.1096/fj.202001607r

Cited by 67 publications

(50 citation statements)

References 163 publications

(203 reference statements)

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“…As novel functions and interactions are discovered almost on a daily basis, the receptors here reviewed can possibly contribute to the understanding of the inflammatory process in the SARS-CoV-2 lung pathogenesis. The presence of mtDNA in cytosol or in the extracellular environment is highly associated with an exacerbated inflammation in the lungs, one of the principal clinical manifestations of SARS-CoV-2 [ 28 , 110 - 113 ]. Furthermore, a vast number of the receptors reviewed here are directly associated with lung inflammatory diseases [ 111 , 112 ].…”

Section: Discussionmentioning

confidence: 99%

Through DNA sensors and hidden mitochondrial effects of SARS-CoV-2

Targhetta

Amaral

Câmara

2021

J. Venom. Anim. Toxins incl. Trop. Dis

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The COVID-19 pandemic brought attention to studies about viral infections and their impact on the cell machinery. SARS-CoV-2, for example, invades the host cells by ACE2 interaction and possibly hijacks the mitochondria. To better understand the disease and to propose novel treatments, crucial aspects of SARS-CoV-2 enrolment with host mitochondria must be studied. The replicative process of the virus leads to consequences in mitochondrial function, and cell metabolism. The hijacking of mitochondria, on the other hand, can drive the extrusion of mitochondrial DNA (mtDNA) to the cytosol. Extracellular mtDNA evoke robust proinflammatory responses once detected, that may act in different pathways, eliciting important immune responses. However, few receptors are validated and are able to detect and respond to mtDNA. In this review, we propose that the mtDNA and its detection might be important in the immune process generated by SARS-CoV-2 and that this mechanism might be important in the lung pathogenesis seen in clinical symptoms. Therefore, investigating the mtDNA receptors and their signaling pathways might provide important clues for therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Through DNA sensors and hidden mitochondrial effects of SARS-CoV-2

Targhetta

Amaral

Câmara

2021

J. Venom. Anim. Toxins incl. Trop. Dis

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“…For example, STING is important for many non-infection-related inflammatory states by mediating acute and chronic inflammatory injury and participating in the onset and progression of auto-inflammatory diseases ( 49 ). Strikingly, many studies have confirmed that not nuclear DNA but mtDNA is the key factor for triggering the cGAS–cGAMP–STING pathway, possibly because mtDNA has fewer DNA repair systems than nuclear DNA and is more prone to damage ( 50 – 54 ).…”

Section: Mechanisms Contributing To the Mtdna-associated Pathogenesis Of Akimentioning

confidence: 99%

Circulating Mitochondrial DNA Stimulates Innate Immune Signaling Pathways to Mediate Acute Kidney Injury

Liu

Gong

2021

Front. Immunol.

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Mitochondrial dysfunction is increasingly considered as a critical contributor to the occurrence and progression of acute kidney injury (AKI). However, the mechanisms by which damaged mitochondria mediate AKI progression are multifactorial and complicated. Mitochondrial DNA (mtDNA) released from damaged mitochondria could serve as a danger-associated molecular pattern (DAMP) and activate the innate immune system through STING, TLR9, NLRP3, and some other adaptors, and further mediate tubular cell inflammation and apoptosis. Accumulating evidence has demonstrated the important role of circulating mtDNA and its related pathways in the progression of AKI, and regulating the proteins involved in these pathways may be an effective strategy to reduce renal tubular injury and alleviate AKI. Here, we aim to provide a comprehensive overview of recent studies on mtDNA-mediated renal pathological events to provide new insights in the setting of AKI.

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“…Physiological responses in a living organism require simultaneous interactions of various microbial products with diverse receptors [24]. STING is a critical and essential innate immune signaling adaptor molecule, which detects exogenous cytosolic doublestranded DNAs (dsDNA) or endogenous sources such as cyclic dinucleotides that have escaped DNase degradation, leading to the production of IFNs [25][26][27][28]. As the DNAs of most microorganisms (except for RNA viruses) and CDNs are considered to be PAMPs, sensing of cyclic dinucleotides by STING connects microbial cytosolic sensing with host cell activation, and gives STING a key role in host immune response [29,30].…”

Section: Intracellular Nucleic Acid Receptors In Mammalian Cells and The Sting/tbk1/irf3 Pathwaymentioning

confidence: 99%

“…In order to avoid continuous innate immune-related pro-inflammatory cytokine expression, STING is controlled by negative feedback and rapidly subjected to degradation [29,38]. This makes the STING pathway an important regulator of host defense against pathogens, in addition to its essential role in protecting the host tissues from the development of cancer [28,30].…”

Section: Intracellular Nucleic Acid Receptors In Mammalian Cells and The Sting/tbk1/irf3 Pathwaymentioning

confidence: 99%

Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

et al. 2021

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Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

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The cGAS‐STING pathway: The role of self‐DNA sensing in inflammatory lung disease

Cited by 67 publications

References 163 publications

Through DNA sensors and hidden mitochondrial effects of SARS-CoV-2

Through DNA sensors and hidden mitochondrial effects of SARS-CoV-2

Circulating Mitochondrial DNA Stimulates Innate Immune Signaling Pathways to Mediate Acute Kidney Injury

Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

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