First Department of Internal Medicine, University Hospital of Alexandroupolis, and.
Laboratory of Molecular Hematology, Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.
J Clin Invest. 2020 Nov 2;130(11):6151-6157. doi: 10.1172/JCI141374.
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.
新出现的数据表明，补体和中性粒细胞有助于导致过度炎症和血栓性微血管病的适应性免疫反应，从而增加 2019 年冠状病毒病（COVID-19）的死亡率。在这里，我们使用 COVID-19 标本、基于细胞的抑制研究和 NET/人主动脉内皮细胞（HAEC）共培养物，研究了补体如何与血小板/中性粒细胞细胞外陷阱（NET）/凝血酶轴相互作用。患者的血浆 NETs、组织因子（TF）活性和 sC5b-9 水平升高。患者的中性粒细胞表达高水平的 TF 并释放携带活性 TF 的 NET。用富含 COVID-19 血小板的血浆处理对照中性粒细胞可产生携带 TF 的 NET，诱导 HAEC 的血栓形成活性。凝血酶或 NETosis 抑制或 C5aR1 阻断可减弱血小板介导的 NET 驱动的血栓形成。COVID-19 血清在体外诱导补体激活，与临床样本中高补体活性一致。用 compstatin Cp40 抑制补体 C3 可破坏中性粒细胞中的 TF 表达。总之，我们为补体和 NET 在 COVID-19 免疫血栓形成中的关键作用提供了机制基础。该研究支持利用补体或 NETosis 抑制来对抗严重急性呼吸综合征冠状病毒 2 的策略。
