TMEM173 Drives Lethal Coagulation in Sepsis

Zhang, Hui; Zeng, Ling; Xie, Min; Liu, Jiao; Zhou, Borong; Wu, Runliu; Cao, Lizhi; Kroemer, Guido; Wang, Haichao; Billiar, Timothy R.; Zeh, Herbert J.; Kang, Rui; Jiang, Jianxin; Yu, Yan; Tang, Daolin

doi:10.1016/j.chom.2020.02.004

Cited by 139 publications

(135 citation statements)

References 106 publications

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“…Among them, pyroptosis is a widely studied form of pro-inflammatory cell death in immune cells as well as epithelial cells that is implicated in various infectious diseases, including viral infections [53,54]. An excessive activation of pyroptosis mainly through inflammatory caspase 1 (CASP1) and caspase 11 (CASP11) (CASP4 and CASP5 in humans) can cause the cleavage of gasdermin D (GSDMD), which produces an N-terminal domain (GSDMD-N) to trigger cell death and the release of pro-inflammatory cytokines (e.g., IL1 and IL18) and DAMPs (e.g., high-mobility group Box 1 [HMGB1] and coagulation factor III [F3; also known as tissue factor]) [53][54][55][56][57][58][59][60]. This process is further modulated by many factors, such as Ca 2+ influx, K + efflux, and lipid peroxidation.…”

Section: Host Cell Deathmentioning

confidence: 99%

“…GSDMD-N-mediated pyroptosis links canonical and noncanonical inflammasome activation to various immune responses and serves as a new target for the treatment of infectious diseases [61]. Indeed, GSDMD-deficient or -mutant mice are resistant to cecal ligation and puncture-induced septic shock or endotoxin lethality [53,54,57,58,60,62,63]. It is likely that a GSDMD inhibitor may limit virus-mediated host cell death.…”

Section: Host Cell Deathmentioning

confidence: 99%

“…However, the excessive activation of TMEM173 can produce type I interferon (IFNα and IFNβ) and various cytokines (e.g., IL6 and TNF), which cause a cytokine storm [99][100][101][102][103][104][105]. The excessive activation of TMEM173 also triggers inflammasome activation [106], GSDMD-N-mediated pyroptosis and subsequent lethal immunocoagulation response in experimental septic shock [60]. Notably, bat is resistant to various viral infections partly due to the loss of TMEM173-mediated type I interferon production [107].…”

Section: Transmembrane Protein 173mentioning

confidence: 99%

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The hallmarks of COVID-19 disease

2020

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus that has caused a worldwide pandemic of the human respiratory illness COVID-19, resulting in a severe threat to public health and safety. Analysis of the genetic tree suggests that SARS-CoV-2 belongs to the same Betacoronavirus group as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Although the route for viral transmission remains a mystery, SARS-CoV-2 may have originated in an animal reservoir, likely that of bat. The clinical features of COVID-19, such as fever, cough, shortness of breath, and fatigue, are similar to those of many acute respiratory infections. There is currently no specific treatment for COVID-19, but antiviral therapy combined with supportive care is the main strategy. Here, we summarize recent progress in understanding the epidemiological, virological, and clinical characteristics of COVID-19 and discuss potential targets with existing drugs for the treatment of this emerging zoonotic disease.

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Section: Host Cell Deathmentioning

confidence: 99%

Section: Host Cell Deathmentioning

confidence: 99%

Section: Transmembrane Protein 173mentioning

confidence: 99%

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The hallmarks of COVID-19 disease

2020

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“…Second, in severe COVID-19, IFN-β might not be the sole explanation for the hyper-coagulation and pro-coagulant activity of TF. Indeed, a recent work showed that activation of STING in monocytes-macrophages during sepsis can also induce hyper-coagulability through the release of TF independently of IFN secretion [55]. The pyroptosis pathway used (STING-ITPR1-calcium release-gasdermin D-pyroptosis-TF) does not rely on the classical components of the STING pathway.…”

Section: Overactivation Of the Sting Pathway Promotes Hypercoagulabilmentioning

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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“…Emerging evidence suggests that GSDMD-dependent pyroptosis induced by caspase-1/11 inflammasome activation drives sepsis downstream of LPS exposure/TMEM173 activation/lipid peroxidation. [70][71][72][73] In addition, magnesium, cAMP and vitamin E can protect against sepsis by blocking GSDMD-induced pyroptosis 70,74,75 These results provide novel insight into the role of GSDMDtriggered pyroptosis in sepsis, thereby revealing some potential targets for therapeutic intervention for lethal infection.…”

Section: Septic Shockmentioning

confidence: 92%

Emerging insights on the role of gasdermins in infection and inflammatory diseases

Tang

Zheng

et al. 2020

Clin & Trans Imm

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The gasdermins, family of pore-forming proteins, are emerging key regulators of infection, autoinflammation and antitumor immunity. Multiple studies have recently characterised their crucial roles in driving pyroptosis, a lytic pro-inflammatory type of cell death. Additionally, gasdermins also act as key effectors of NETosis, secondary necrosis and apoptosis. In this review, we will address current understanding of the mechanisms of gasdermin activation and further describe the protective and detrimental roles of gasdermins in host defence and autoinflammatory diseases. These data suggest that gasdermins play a prominent role in innate immunity and autoinflammatory disorders, thereby providing potential new therapeutic avenues for the treatment of infection and autoimmune disease.

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TMEM173 Drives Lethal Coagulation in Sepsis

Cited by 139 publications

References 106 publications

The hallmarks of COVID-19 disease

The hallmarks of COVID-19 disease

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

Emerging insights on the role of gasdermins in infection and inflammatory diseases

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