IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome

Kang, Sujin; Tanaka, Toshio; Inoue, Hiroshige; Ono, Chikako; Hirano, Shoji; Kioi, Yoshiyuki; Matsumoto, Hisatake; Mizunuma, Hiroshi; Matsubara, Tsunehiro; Shimizu, Kentaro; Ogura, Hiroshi; Matsuura, Yoshiharu; Kishimoto, Tadamitsu

doi:10.1073/pnas.2010229117

Cited by 250 publications

(238 citation statements)

References 32 publications

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“…2 ) [ 72 ]. In addition, IL-6 trans -signaling increases IL-8 production in SARS-COV-2 infection but the precise signaling pathway is still unknown [ 73 ].…”

Section: How Does Sars-cov-2 Initiate Cytokine Release and What Are Tmentioning

confidence: 99%

The pro-inflammatory cytokines in COVID-19 pathogenesis: What goes wrong?

Darif

Hammi

Kihel

et al. 2021

Microbial Pathogenesis

256

195

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The outbreak of coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, has emerged in China in December 2019 and rapidly spread to more than 196 countries worldwide. The physiopathology of human SARS-CoV-2 has not been completely understood, but its pathogenesis has been linked to a disproportionate response of the immune system. Just as described for SARS and MERS, an uncontrolled systemic inflammatory response, known as cytokine release syndrome (CRS) was observed in severe COVID-19 patients. It results from the release by immune and non-immune effector cells of substantial amounts of pro-inflammatory cytokines and appears to contribute to SARS-CoV-2 pulmonary inflammation and extensive lung damage. In addition, hyper-coagulation and thrombosis resulted from the important release of pro-inflammatory cytokines contribute to the lethality of subjects severely infected with SARS-CoV-2. It is therefore essential to have a deep understanding of the various cytokines involved in this exacerbated immune response, and that could be targeted by potential immunological treatments. The aim of this review was to gather the current knowledge about the role of pro-inflammatory cytokines, namely IL-1β, IL-6, IL-8, IL-17 and TNFα in SARS-CoV-2 CRS , the probable causes and clinical outcomes of this phenomenon in severe cases of COVID-19.

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“…2 ) [ 72 ]. In addition, IL-6 trans -signaling increases IL-8 production in SARS-COV-2 infection but the precise signaling pathway is still unknown [ 73 ].…”

Section: How Does Sars-cov-2 Initiate Cytokine Release and What Are Tmentioning

confidence: 99%

The pro-inflammatory cytokines in COVID-19 pathogenesis: What goes wrong?

Darif

Hammi

Kihel

et al. 2021

Microbial Pathogenesis

256

195

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“…Certainly, one can say that markers such as IL-6 are now commonly used as predictors of COVID-19 severity (Del Valle et al, 2020), although this is not universally accepted (Mudd et al, 2020). In vitro data indicate that IL-6 induces the production of PAI-1 in cultured cells, while the inhibition of IL-6 signaling has been shown to reduce PAI-1 levels in COVID-19 patients (Kang et al, 2020).…”

Section: Pai-1 and T-pamentioning

confidence: 99%

High levels of plasminogen activator inhibitor-1, tissue plasminogen activator and fibrinogen in patients with severe COVID-19

Cabrera-Garcia

Miltiades²,

Parsons³

et al. 2021

Preprint

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We measured plasma levels of fibrinogen, plasminogen, tissue plasminogen activator (t-PA) and plasminogen activation inhibitor 1 (PAI-1) in blood from 37 patients with severe coronavirus disease-19 (COVID-19) and 23 controls. PAI-1, t-PA and fibrinogen levels were significantly higher in the COVID-19 group. Increased levels of PAI-1 likely result in lower plasmin activity and hence decreased fibrinolysis. These observations provide a partial explanation for the fibrin-mediated increase in blood viscosity and hypercoagulability that has previously been observed in COVID-19. Our data suggest that t-PA administration may be problematic, but that other interventions designed to enhance fibrinolysis might prove useful in the treatment of the coagulopathy that is often associated with severe COVID-19.

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“…Another pathognomonic sign of COVID-19 is CRS, which seems to be mediated by an inflammation circuit due to IL-6 trans-signaling causing endotheliopathy. 9 Thus, we evaluated if there was a temporal association between NET and VWF/ADAMTS13axis dynamics, and IL-6 levels. For this, we analyzed those parameters in the maximal and nadir values of IL-6 in 19 patients.…”

mentioning

confidence: 99%

Neutrophil extracellular traps and von Willebrand factor are allies that negatively influence COVID‐19 outcomes

Fernández-Pérez

Águila

Reguilón-Gallego

et al. 2021

Clinical & Translational Med

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Dear Editor, Complex interactions between various processes have arisen as key elements underlying the pathophysiology of coronavirus disease 2019 (COVID-19). First, immunothrombosis and neutrophil extracellular trap (NET) release contribute to inflammation-associated lung damage and thrombosis, and second, endothelial cell dysfunction participates in the disease-associated coagulopathy. 1,2 In addition, cytokine release syndrome (CRS) dictates adverse clinical outcomes, with interleukin (IL)-6 playing a central role. 3 However, the sequence of events leading to a vicious cycle of synergistic pathways causing unchecked immune activation and thrombus formation have to date not been clearly defined. Here, we investigated the role of NETs, endotheliopathy, hemostatic imbalance, and interleukin-6 (IL-6) release in the severity of the disease, as well as their synergy in patient outcomes. For this purpose, we recruited 142 hospitalized COVID-19 patients from March to May 2020. Infection was confirmed by qRT-PCR testing. Healthy controls (HC, N = 50) were also included. Clinical and demographical variables are reported in Table S1, and biochemical analytical data and cell counts in Table S2. To address whether NETs and von Willebrand factor (VWF)/a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) axis are associated and contribute to the prognosis of COVID-19 patients, we analyzed plasma cell-free DNA (cfDNA), citrullinated histone H3-DNA (citH3-DNA) complexes (surrogated NET marker), von Willebrand factor antigen (VWF:Ag), von Willebrand factor collagen binding (VWF:CB), ADAMTS13 activity, IL-6 levels, clinical scores, and outcomes. Analysis of NETosis and endotheliopathy markers in the first available sample confirmed a coagulation imbalance in COVID-19 patients versus HC (Figure S1A-F). In addition, NETs and VWF:Ag correlated with neutrophil count, neutrophil/lymphocyte ratio, and with acute-phase reactants and coagulation parameters (Table S3). Importantly, NETs and VWF:Ag/ADAMTS13 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome

Cited by 250 publications

References 32 publications

The pro-inflammatory cytokines in COVID-19 pathogenesis: What goes wrong?

The pro-inflammatory cytokines in COVID-19 pathogenesis: What goes wrong?

High levels of plasminogen activator inhibitor-1, tissue plasminogen activator and fibrinogen in patients with severe COVID-19

Neutrophil extracellular traps and von Willebrand factor are allies that negatively influence COVID‐19 outcomes

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