Complement and tissue factor–enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis
Panagiotis Skendros, … , John D. Lambris, Konstantinos Ritis
Panagiotis Skendros, … , John D. Lambris, Konstantinos Ritis
Published August 6, 2020
Citation Information: J Clin Invest. 2020;130(11):6151-6157. https://doi.org/10.1172/JCI141374.
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Concise Communication COVID-19 Immunology

Complement and tissue factor–enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis

Abstract

Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.

Authors

Panagiotis Skendros, Alexandros Mitsios, Akrivi Chrysanthopoulou, Dimitrios C. Mastellos, Simeon Metallidis, Petros Rafailidis, Maria Ntinopoulou, Eleni Sertaridou, Victoria Tsironidou, Christina Tsigalou, Maria Tektonidou, Theocharis Konstantinidis, Charalampos Papagoras, Ioannis Mitroulis, Georgios Germanidis, John D. Lambris, Konstantinos Ritis

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Figure 4

Proposed mechanism of COVID-19 immunothrombosis.

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Proposed mechanism of COVID-19 immunothrombosis. During COVID-19, SARS–C...
During COVID-19, SARS–CoV-2 triggers complement activation by interacting with mannan-binding lectin (MBL) serine proteases (MASPs) or possibly through (auto)antibodies or/and immunocomplexes. C3 activation, as a point of convergence of all complement pathways, leads to C3a, C5a, and sC5b-9 (TCC) generation. Subsequently, C3a might activate platelets (PLTs), while C5a and PLT-derived thrombin induce both neutrophil TF expression and NETs carrying active TF. These thrombogenic NETs may induce endothelial cell activation toward TF expression, thus increasing their procoagulant activity. This may further amplify (e.g., via PAR1), inflammation and PLT activation, thereby fueling a complement/NET-driven vicious cycle of immunothrombosis. Complement, thrombin, and NETosis represent promising therapeutic targets. The central pink box includes components of the COVID-19 thromboinflammatory environment. Question marks and dotted lines indicate provisional pathways/connections that have not yet been investigated in COVID-19. FP, properdin; PMX-53, specific C5a receptor antagonist.