NLRP3 inflammasome and interleukin-1 contributions to COVID-19-associated coagulopathy and immunothrombosis.
NLRP3 inflammasome and interleukin-1 contributions to COVID-19-associated coagulopathy and immunothrombosis.
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NLRP3 炎性体和白细胞介素 1 对 COVID-19 相关凝血病和免疫血栓形成的贡献。
DOI：
10.1093/cvr/cvad084
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发表时间：
2023
影响因子：
10.8
通讯作者：
Abbate,Antonio
中科院分区：
文献类型：
--
作者：
Potere,Nicola;Garrad,Evan;Kanthi,Yogendra;DiNisio,Marcello;Kaplanski,Gilles;Bonaventura,Aldo;Connors,JeanMarie;DeCaterina,Raffaele;Abbate,Antonio
免疫血栓形成--免疫介导的凝血激活--对病原体具有保护作用，但过度的免疫血栓形成可导致病理性血栓形成和多器官损伤，如2019年严重冠状病毒病（COVID-19）。含NACHT、LRR和pyrin结构域的蛋白3（NLRP 3）炎性体产生白细胞介素（IL）-1家族的主要促炎细胞因子IL-1β和IL-18，并诱导焦变性细胞死亡。NLRP 3炎性体途径的激活还促进免疫血栓形成程序，包括白细胞释放中性粒细胞胞外陷阱和组织因子，以及血小板和血管内皮的促血栓形成反应。NLRP 3炎性小体激活发生在COVID-19肺炎患者中。在临床前模型中，NLRP 3炎性体通路阻断抑制COVID-19样过度炎症和病理。阿那白滞素是重组人IL-1受体拮抗剂，显示出安全性和有效性，并被批准用于治疗具有早期炎症过度体征的低氧血症COVID-19患者。非选择性NLRP 3抑制剂秋水仙碱减少了COVID-19门诊患者亚组的住院和死亡，但未被批准用于治疗COVID-19。测试NLRP 3炎性体通路阻断剂的其他COVID-19试验尚不确定或正在进行中。我们在此概述了免疫血栓形成对COVID-19相关凝血病的贡献，并回顾了表明NLRP 3炎性小体通路参与COVID-19免疫血栓形成发病机制的临床前和临床证据。我们还总结了目前在COVID-19中靶向NLRP 3炎性体通路的努力，并讨论了挑战，未满足的差距以及炎性体靶向策略可能为炎症驱动的血栓性疾病（包括COVID-19）提供的治疗潜力。
Immunothrombosis—immune-mediated activation of coagulation—is protective against pathogens, but excessive immunothrombosis can result in pathological thrombosis and multiorgan damage, as in severe coronavirus disease 2019 (COVID-19). The NACHT-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome produces major proinflammatory cytokines of the interleukin (IL)-1 family, IL-1β and IL-18, and induces pyroptotic cell death. Activation of the NLRP3 inflammasome pathway also promotes immunothrombotic programs including release of neutrophil extracellular traps and tissue factor by leukocytes, and prothrombotic responses by platelets and the vascular endothelium. NLRP3 inflammasome activation occurs in patients with COVID-19 pneumonia. In preclinical models, NLRP3 inflammasome pathway blockade restrains COVID-19-like hyperinflammation and pathology. Anakinra, recombinant human IL-1 receptor antagonist, showed safety and efficacy and is approved for the treatment of hypoxaemic COVID-19 patients with early signs of hyperinflammation. The non-selective NLRP3 inhibitor colchicine reduced hospitalization and death in a subgroup of COVID-19 outpatients but is not approved for the treatment of COVID-19. Additional COVID-19 trials testing NLRP3 inflammasome pathway blockers are inconclusive or ongoing. We herein outline the contribution of immunothrombosis to COVID-19-associated coagulopathy, and review preclinical and clinical evidence suggesting an engagement of the NLRP3 inflammasome pathway in the immunothrombotic pathogenesis of COVID-19. We also summarize current efforts to target the NLRP3 inflammasome pathway in COVID-19, and discuss challenges, unmet gaps, and the therapeutic potential that inflammasome-targeted strategies may provide for inflammation-driven thrombotic disorders including COVID-19.