Journal Article

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

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

2020

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Aged / Aorta / Autophagy / Betacoronavirus - immunology / Betacoronavirus - metabolism / Biomedical research / Complement activation / Complement Activation - drug effects / Complement component C3 / Complement Membrane Attack Complex - immunology / Complement Membrane Attack Complex - metabolism / Complement system / Complications and side effects / Concise Communication / Coronaviridae / Coronavirus Infections - blood / Coronavirus Infections - immunology / Coronaviruses / COVID-19 / Development and progression / Endothelial cells / Extracellular Traps - immunology / Extracellular Traps - metabolism / Female / Health aspects / Humans / Immune response / Investigations / Leukocytes (neutrophilic) / Male / Middle Aged / Mortality / Neutrophils / Neutrophils - immunology / Neutrophils - metabolism / Pandemics / Patients / Peptides, Cyclic - pharmacology / Plasma / Plasma levels / Platelets / Pneumonia, Viral - blood / Pneumonia, Viral - immunology / Receptor, Anaphylatoxin C5a - antagonists & inhibitors / Receptor, Anaphylatoxin C5a - blood / Receptor, Anaphylatoxin C5a - immunology / Respiratory Distress Syndrome - blood / Respiratory Distress Syndrome - immunology / Respiratory Distress Syndrome - virology / Risk factors / SARS-CoV-2 / Severe acute respiratory syndrome coronavirus 2 / Thrombin / Thrombin - immunology / Thrombin - metabolism / Thromboplastin - immunology / Thromboplastin - metabolism / Thrombosis / Thrombosis - blood / Thrombosis - immunology / Thrombosis - virology / Thrombotic microangiopathy / Tissue factor