P. Skendros, A. Mitsios, A. Chrysanthopoulou, D. Mastellos, S. Metallidis, P. Rafailidis, M. Ntinopoulou, E. Sertaridou, V. Tsironidou, C. Tsigalou, M. Tektonidou, T. Konstantinidis, C. Papagoras, I. Mitroulis, G. Germanidis, J. Lambris, K. Ritis
The Journal of clinical investigation, 2020
Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyper-inflammation and thrombotic microangiopathy, thereby increasing 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 NETs/human aortic endothelial cell (HAEC) co-cultures. 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 HAEC. 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 SARS-CoV-2 that exploit complement or NETosis inhibition.
Cited by 97 publications.
Field of study: Medicine