Τίτλος:
Complement and tissue factor–enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. Copyright: © 2020, American Society for Clinical Investigation.
Συγγραφείς:
Skendros, P.
Mitsios, A.
Chrysanthopoulou, A.
Mastellos, D.C.
Metallidis, S.
Rafailidis, P.
Ntinopoulou, M.
Sertaridou, E.
Tsironidou, V.
Tsigalou, C.
Tektonidou, M.
Konstantinidis, T.
Papagoras, C.
Mitroulis, I.
Germanidis, G.
Lambris, J.D.
Ritis, K.
Περιοδικό:
JOURNAL OF CLINICAL INVESTIGATION
Εκδότης:
American Society for Clinical Investigation
Λέξεις-κλειδιά:
complement; thrombin; thromboplastin; C5AR1 protein, human; complement component C5a receptor; complement membrane attack complex; compstatin; cyclopeptide; thrombin; thromboplastin, adult; aortic endothelial cell; Article; clinical article; complement activation; coronavirus disease 2019; extracellular trap; female; human; in vitro study; male; neutrophil; priority journal; protein expression; protein interaction; thrombocyte rich plasma; thrombogenicity; thrombosis; adult respiratory distress syndrome; aged; Betacoronavirus; blood; clinical trial; Coronavirus infection; drug effect; immunology; metabolism; middle aged; neutrophil; pandemic; virology; virus pneumonia, Aged; Betacoronavirus; Complement Activation; Complement Membrane Attack Complex; Coronavirus Infections; Extracellular Traps; Female; Humans; Male; Middle Aged; Neutrophils; Pandemics; Peptides, Cyclic; Pneumonia, Viral; Receptor, Anaphylatoxin C5a; Respiratory Distress Syndrome, Adult; Thrombin; Thromboplastin; Thrombosis
