Department of Vascular Surgery, The 2nd Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
Department of Cardiology, The 2nd Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
Biochem Biophys Res Commun. 2021 Aug 6;565:64-71. doi: 10.1016/j.bbrc.2021.05.091. Epub 2021 Jun 4.
Neutrophil extracellular traps (NETs) are extracellular webs of DNA, histones and granular contents that are released by neutrophils to control infections. However, NETs that is not properly regulated can propagate inflammation and thrombosis. It was recognized that viruses can induce NETs. As a synthetic analog of viral double-stranded (ds) RNA, polyinosinic-polycytidylic acid [poly(I:C)] is known to induce inflammation and thrombosis. However, whether and how poly(I:C) modulates NETs remains unclear. Here, we have demonstrated that poly(I:C) induced extracellular DNA traps in human neutrophils in a dose-dependent manner. Further, poly(I:C) or dsRNA virus elevated the levels of myeloperoxidase-DNA complexes and citrullinated histone H3, which are specific markers of NETs, in both neutrophil supernatants and mouse plasma. Interestingly, a potent peptidylarginine deiminase 4 (PAD4) inhibitor, BB-CL-Amidine (BB-CLA) or PAD4 knockdown effectively prevented poly(I:C)-induced NETs formation and release. In addition, BB-CLA abrogated poly(I:C)-triggered neutrophil activation and infiltration, and vascular permeability in lungs. BB-CLA also attenuated poly(I:C)-induced thrombocytopenia in circulation, fibrin deposition and thrombus formation in tissues. Taken together, these results suggest that viral mimetic poly(I:C) may induce NETs-dependent inflammation and thrombosis through PAD4, and that inhibiting PAD4 may become a good strategy to protect against viral infection-caused inflammation/thrombosis-related pathological conditions of diseases.
中性粒细胞胞外诱捕网（NETs）是由中性粒细胞释放的一种 DNA、组蛋白和颗粒内容物的细胞外网络，用于控制感染。然而，未被适当调节的 NETs 会引发炎症和血栓形成。人们已经认识到病毒可以诱导 NETs 的形成。聚肌苷酸-聚胞苷酸[poly(I:C)]作为病毒双链 (ds) RNA 的合成类似物，已知可诱导炎症和血栓形成。然而，poly(I:C) 是否以及如何调节 NETs 尚不清楚。在这里，我们已经证明 poly(I:C) 以剂量依赖的方式诱导人中性粒细胞释放细胞外 DNA 陷阱。此外，poly(I:C) 或 dsRNA 病毒增加了中性粒细胞上清液和小鼠血浆中髓过氧化物酶-DNA 复合物和瓜氨酸化组蛋白 H3 的水平，这是 NETs 的特异性标志物。有趣的是，一种有效的肽基精氨酸脱亚氨酶 4 (PAD4) 抑制剂 BB-CL-Amidine (BB-CLA) 或 PAD4 敲低可有效阻止 poly(I:C) 诱导的 NETs 形成和释放。此外，BB-CLA 可阻断 poly(I:C) 触发的中性粒细胞活化和浸润，以及肺部血管通透性。BB-CLA 还可减轻 poly(I:C) 引起的循环血小板减少、组织中纤维蛋白沉积和血栓形成。综上所述，这些结果表明，病毒模拟物 poly(I:C) 可能通过 PAD4 诱导 NETs 依赖性炎症和血栓形成，抑制 PAD4 可能成为预防病毒感染引起的炎症/血栓形成相关疾病病理状况的一种有效策略。
