STING is an essential regulator of heart inflammation and fibrosis in mice with pathological cardiac hypertrophy via endoplasmic reticulum (ER) stress

Zhang, Yan; Chen, Wenzhong; Wang, Yan

doi:10.1016/j.biopha.2020.110022

Cited by 112 publications

(108 citation statements)

References 50 publications

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“…Angiotensin II induced STING expression and increased IFN in cardiac myocytes in an ER stress dependent manner. In this study, STING-/-mice exhibited decreased ER stress following aortic banding (166). Moretti et al described STING activated ER stress and autophagy induction in the setting of Listeria innocua infection.…”

Section: Sting and The Er: Cross Talk And Cross Regulationsupporting

confidence: 59%

STING, the Endoplasmic Reticulum, and Mitochondria: Is Three a Crowd or a Conversation?

Smith

2021

Front. Immunol.

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The anti-viral pattern recognition receptor STING and its partnering cytosolic DNA sensor cGAS have been increasingly recognized to respond to self DNA in multiple pathologic settings including cancer and autoimmune disease. Endogenous DNA sources that trigger STING include damaged nuclear DNA in micronuclei and mitochondrial DNA (mtDNA). STING resides in the endoplasmic reticulum (ER), and particularly in the ER-mitochondria associated membranes. This unique location renders STING well poised to respond to intracellular organelle stress. Whereas the pathways linking mtDNA and STING have been addressed recently, the mechanisms governing ER stress and STING interaction remain more opaque. The ER and mitochondria share a close anatomic and functional relationship, with mutual production of, and inter-organelle communication via calcium and reactive oxygen species (ROS). This interdependent relationship has potential to both generate the essential ligands for STING activation and to regulate its activity. Herein, we review the interactions between STING and mitochondria, STING and ER, ER and mitochondria (vis-à-vis calcium and ROS), and the evidence for 3-way communication.

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Section: Sting and The Er: Cross Talk And Cross Regulationsupporting

confidence: 59%

STING, the Endoplasmic Reticulum, and Mitochondria: Is Three a Crowd or a Conversation?

Smith

2021

Front. Immunol.

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“…Excessive STING activity induces pyroptosis in monocytes and macrophages, as well as elevated tissue factor (CD142) levels ( 136), both of which occur in severe COVID-19 patients (73,137,138). The overexpression of angiotensin-II activates the STING pathway in murine myocardial cells (139), which may indicate a route by which STING is overstimulated in COVID-19 patients with cardiovascular disease and T2DM. These rapid responses stimulate different effects, depending on the cell type in which they occur [reviewed in (140)].…”

Section: Overview Of Immune Response To Sars-cov-2 Infectionmentioning

confidence: 99%

Why Is COVID-19 More Severe in Patients With Diabetes? The Role of Angiotensin-Converting Enzyme 2, Endothelial Dysfunction and the Immunoinflammatory System

Roberts

Pritchard

Treweeke

et al. 2021

Front. Cardiovasc. Med.

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Meta-analyses have indicated that individuals with type 1 or type 2 diabetes are at increased risk of suffering a severe form of COVID-19 and have a higher mortality rate than the non-diabetic population. Patients with diabetes have chronic, low-level systemic inflammation, which results in global cellular dysfunction underlying the wide variety of symptoms associated with the disease, including an increased risk of respiratory infection. While the increased severity of COVID-19 amongst patients with diabetes is not yet fully understood, the common features associated with both diseases are dysregulated immune and inflammatory responses. An additional key player in COVID-19 is the enzyme, angiotensin-converting enzyme 2 (ACE2), which is essential for adhesion and uptake of virus into cells prior to replication. Changes to the expression of ACE2 in diabetes have been documented, but they vary across different organs and the importance of such changes on COVID-19 severity are still under investigation. This review will examine and summarise existing data on how immune and inflammatory processes interplay with the pathogenesis of COVID-19, with a particular focus on the impacts that diabetes, endothelial dysfunction and the expression dynamics of ACE2 have on the disease severity.

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“…Interestingly, it has been shown on cultured murine myocardial cells that addition of angiotensin II induced a strong expression of STING, this expression being still accelerated by endoplasmic reticulum stress activator [45]. Therefore, excessive angiotensin II signaling in COVID-19 due to poor ACE2 conversion of angiotensin II at the cell surface, could contribute to activate the STING pathway (Figure).…”

Section: The Binding Of Sars-cov2 To Ace2 Could Directly Activate Thementioning

confidence: 99%

Kawasaki-like diseases and thrombotic coagulopathy in COVID-19: delayed over-activation of the STING pathway?

Berthelot

Drouet

Lioté

2020

Emerging Microbes & Infections

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We previously made the hypothesis that STING contributes to COVID-19. The present review detail new arguments for over-activation of STING pathways in COVID-19, following the description of hyper-coagulability and Kawasaki-like diseases in children. Indeed, Kawasaki disease is induced by overreaction of innate cells following exposition to various viruses, including herpes viruses which trigger STING. It predisposes to diffuse vasculitis and aneurysms, whereas STING is over-expressed in arterial aneurisms. The redness at the inoculation site of bacillus Calmette-Guérin, a specific feature of Kawasaki disease, is reproduced by activation of the STING pathway, which is inhibited upstream by aspirin, intravenous immunoglobulins, and Vitamin-D. SARS-CoV2 binding to ACE2 can lead to excessive angiotensin II signaling, which activates the STING pathway in mice. Over-activation of the STING-pathway promotes hyper-coagulability through release of interferon-β and tissue factor by monocytes-macrophages. Aspirin and dipyridamole, besides their anti-platelet activity, also reduce tissue factor procoagulant activity, and aspirin inhibits the STING pathway upstream of STING. Aspirin and dipyridamole may be used, in combination with drugs blocking downstream the activation of the STING pathway, like inhibitors of IL-6R and JAK/STAT pathways. The risk of bleeding should be low as bleeding has not been reported in severe COVID-19 patients. Triggering of the STING pathway by alien or self cytosolic DNA, can activate (from right to left): IRF-3 (partly inhibited by IVIgs after linking of FcγRIIa [38]), NK-κB, and the inflammasome NLRP3 [9]. This might occur even more frequently in COVID-19 patients with simultaneous enhancement of STING synthesis following excess of angiotensin II on cell membrane, secondary to the ACE1/2 imbalance (more pronounced in males), induced by the binding of SARS-CoV2 to ACE2 [42-45].

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STING is an essential regulator of heart inflammation and fibrosis in mice with pathological cardiac hypertrophy via endoplasmic reticulum (ER) stress

Cited by 112 publications

References 50 publications

STING, the Endoplasmic Reticulum, and Mitochondria: Is Three a Crowd or a Conversation?

STING, the Endoplasmic Reticulum, and Mitochondria: Is Three a Crowd or a Conversation?

Why Is COVID-19 More Severe in Patients With Diabetes? The Role of Angiotensin-Converting Enzyme 2, Endothelial Dysfunction and the Immunoinflammatory System

Kawasaki-like diseases and thrombotic coagulopathy in COVID-19: delayed over-activation of the STING pathway?

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