Reactive oxygen species oxidize STING and suppress interferon production

Tao, Lili; Lemoff, Andrew; Zarek, C. M.; Lowe, Alexandria; Yan, Nan; Reese, Tiffany A.

doi:10.7554/elife.57837

Cited by 66 publications

(56 citation statements)

References 67 publications

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“…Moreover, the increase of mtROS led to cGAS-STING induction of type I IFN ( 143 , 144 ). Controversially, during herpesvirus infection ROS were found to dampen the type I IFN production in a STING-dependent manner ( 145 ). To try to reconcile these findings, the authors speculated that the differences could be ascribed to the amount of ROS, as cysteines can be susceptible to different post-translation modifications, which can either activate or inhibit protein function.…”

Section: Targets Of Ros In Macrophagesmentioning

confidence: 99%

Reactive Oxygen Species in Macrophages: Sources and Targets

et al. 2021

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Reactive oxygen species (ROS) are fundamental for macrophages to eliminate invasive microorganisms. However, as observed in nonphagocytic cells, ROS play essential roles in processes that are different from pathogen killing, as signal transduction, differentiation, and gene expression. The different outcomes of these events are likely to depend on the specific subcellular site of ROS formation, as well as the duration and extent of ROS production. While excessive accumulation of ROS has long been appreciated for its detrimental effects, there is now a deeper understanding of their roles as signaling molecules. This could explain the failure of the “all or none” pharmacologic approach with global antioxidants to treat several diseases. NADPH oxidase is the first source of ROS that has been identified in macrophages. However, growing evidence highlights mitochondria as a crucial site of ROS formation in these cells, mainly due to electron leakage of the respiratory chain or to enzymes, such as monoamine oxidases. Their role in redox signaling, together with their exact site of formation is only partially elucidated. Hence, it is essential to identify the specific intracellular sources of ROS and how they influence cellular processes in both physiological and pathological conditions to develop therapies targeting oxidative signaling networks. In this review, we will focus on the different sites of ROS formation in macrophages and how they impact on metabolic processes and inflammatory signaling, highlighting the role of mitochondrial as compared to non-mitochondrial ROS sources.

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Section: Targets Of Ros In Macrophagesmentioning

confidence: 99%

Reactive Oxygen Species in Macrophages: Sources and Targets

et al. 2021

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“…In addition, fibrates and WY14643 induce ROS (36)(37)(38)(39)(40). As we recently reported, the induction of ROS in MHV68-infected cells or cells stimulated via the cGAS/STING pathway reduces production of IFN by impairing STING polymerization (41).…”

Section: Discussionmentioning

confidence: 91%

WY14643 Increases Herpesvirus Replication Independently of PPARα Expression and Inhibits IFNβ Production

Lei

Dryden

Lowe

et al. 2021

Preprint

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Peroxisome proliferator activated receptor (PPAR) agonists are commonly used to treat metabolic disorders in humans because they regulate fatty acid oxidation and cholesterol metabolism. In addition to their roles in controlling metabolism, PPAR agonists also regulate inflammation and are immunosuppressive in models of autoimmunity. We aimed to test whether activation of PPARα with clinically relevant ligands could impact herpesvirus infection using the model strain murine gammaherpesvirus-68. We found that PPARα agonists WY14643 and fenofibrate increased herpesvirus replication in vitro. In vivo, WY14643 increased viral replication and caused lethality in mice. Unexpectedly, these effects proved independent of PPARα. Investigating the mechanism of action for WY14643, we found that it suppresses production of type I interferon by inhibiting stimulator of interferon (STING), which lies downstream of the cytoplasmic DNA sensor cGAS. Thus, WY14643 regulates interferon downstream of cytoplasmic DNA recognition and increases herpesvirus replication in a PPARα-independent manner. Taken together, our data indicate that caution should be employed when using PPARα agonists in immuno-metabolic studies, as they can have off-target effects on viral replication.ImportancePPAR agonists are used clinically to treat both metabolic and inflammatory disorders. Because viruses are known to rewire host metabolism to their own benefit, the intersection of immunity, metabolism, and virology is an important research area. Our article is an important contribution to this field because for two reasons. First, it shows a role for PPARα agonists in altering virus detection by cells. Second, it shows that PPARα agonists can affect virus replication in a manner unrelated to their expected genetic function. This knowledge is valuable for anyone seeking to use PPARα agonists as a research tool.

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“…Consisting with our findings, ROS was once proved to potentiate STING-dependent type I IFN induction in dendritic cells [ 43 ] and Luo et al reported that ROS activated the STING pathway in Aortic smooth muscle cells [ 17 ]. However, cellular oxidative stress by reported can prevent the activation of STING-dependent DNA sensing in macrophages during DNA viral infection in mechanism that oxidized cysteine 178 or 179 on STING induced by ROS [ 44 ]. These seemingly opposing results are likely due to the different cell types utilized.…”

Section: Resultsmentioning

confidence: 99%

Injectable self-healing hydrogel with siRNA delivery property for sustained STING silencing and enhanced therapy of intervertebral disc degeneration

Chen

Zhu

et al. 2022

Bioactive Materials

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Inflammatory responses of nucleus pulposus (NP) can induce imbalanced anabolism and catabolism of extracellular matrix, and the cytosolic dsDNA accumulation and STING–NF–κB pathway activation found in NP inflammation are considered as fairly important cause of intervertebral disc (IVD) degeneration. Herein, we constructed a siSTING delivery hydrogel of aldehyde hyaluronic acid (HA-CHO) and poly(amidoamine) PAMAM/siRNA complex to intervene the abnormal STING signal for IVD degeneration treatment, where the formation of dynamic Schiff base bonds in the system (siSTING@HP gel ) was able to overcome the shortcomings such as low cellular uptake, short half-life, and rapid degradation of siRNA-based strategy. PAMAM not only formed complexes with siRNA to promote siRNA transfection, but also served as dynamic crosslinker to construct hydrogel, and the injectable and self-healing hydrogel efficiently and steadily silenced STING expression in NP cells. Finally, the siSTING@HP gel significantly eased IVD inflammation and slowed IVD degeneration by prolonging STING knockdown in puncture-induced IVD degeneration rat model, revealing that STING pathway was a therapeutic target for IVD degeneration and such novel hydrogel had great potential for being applied to many other diseases for gene delivery.

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Reactive oxygen species oxidize STING and suppress interferon production

Cited by 66 publications

References 67 publications

Reactive Oxygen Species in Macrophages: Sources and Targets

Reactive Oxygen Species in Macrophages: Sources and Targets

WY14643 Increases Herpesvirus Replication Independently of PPARα Expression and Inhibits IFNβ Production

Injectable self-healing hydrogel with siRNA delivery property for sustained STING silencing and enhanced therapy of intervertebral disc degeneration

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