Thromboinflammation: From Atherosclerosis to COVID-19.
Thromboinflammation: From Atherosclerosis to COVID-19.
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DOI：
10.1161/atvbaha.122.317162
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发表时间：
2022-09
影响因子：
8.7
通讯作者：
Heger, Lukas A.
中科院分区：
文献类型：
--
作者：
Wagner, Denisa D.;Heger, Lukas A.
关键词：
血栓形成和炎症(血栓炎症)的激活相互作用已被确定为一种主要的潜在途径，不仅导致心血管疾病，而且还导致自身免疫性疾病，最近导致2019年冠状病毒病(新冠肺炎)。多年来，先天免疫细胞已成为这一过程的重要调节器。作为人类中最丰富的白细胞，中性粒细胞在促进血栓炎症方面处于有利地位。这包括它们通过释放被称为中性粒细胞外陷阱(Net)的去凝集染色质结构来触发有组织的细胞死亡途径的能力。在组蛋白、细胞质和颗粒蛋白的装饰下，Net发挥细胞毒性、免疫原性和促血栓形成作用，加速疾病进展。导致细胞外DNA释放的不同步骤需要蛋白质精氨酸脱亚胺酶4(PAD4)的活性来催化组蛋白的瓜氨酸化，并由中性粒细胞炎症体支持。通过将中性粒细胞的免疫功能与单核细胞和血小板的促凝血和促炎活性联系起来，PAD4的活性对于理解血栓炎症的过程具有重要的意义。我们还将讨论血栓炎症中血管闭塞依赖于Net与超大von Willebrand因子(ULVWF)相互作用的机制，推测PAD4在中性粒细胞炎症小体组装中的重要性，以及Net在包括动脉粥样硬化和新冠肺炎在内的血栓性炎症疾病中的重要性。本文主要关注瓦格纳实验室的工作，是基于2021年罗素·罗斯在血管生物学中的纪念讲座。罗斯教授是丹尼萨·瓦格纳博士的导师，并影响了她的实验室在动脉粥样硬化领域的研究。
The activating interplay of thrombosis and inflammation (thromboinflammation) has been established as a major underlying pathway, driving not only cardiovascular disease but also autoimmune disease, and most recently, Coronavirus disease 2019 (COVID-19). Throughout the years, innate immune cells have emerged as important modulators of this process. As the most abundant white blood cell in humans, neutrophils are well-positioned to propel thromboinflammation. This includes their ability to trigger an organized cell death pathway with release of decondensed chromatin structures called neutrophil extracellular traps (NETs). Decorated with histones and cytoplasmic as well as granular proteins, NETs exert cytotoxic, immunogenic and prothrombotic effects accelerating disease progression. Distinct steps leading to extracellular DNA release (NETosis) require the activities of protein arginine deiminase 4 (PAD4) catalyzing citrullination of histones and are supported by neutrophil inflammasome. By linking the immunological function of neutrophils with the pro-coagulant and pro-inflammatory activities of monocytes and platelets, PAD4 activity holds important implications for understanding the processes that fuel thromboinflammation. We will also discuss mechanisms whereby vascular occlusion in thromboinflammation depends on the interaction of NETs with ultra-large von Willebrand Factor (ULVWF), and speculate on the importance of PAD4 in neutrophil inflammasome assembly and NETs in thromboinflammatory diseases including atherosclerosis and COVID-19. This article, primarily focused on work from the Wagner lab, is based on the 2021 Russell Ross Memorial Lecture in Vascular Biology. Professor Ross was a mentor to Dr Denisa Wagner and influenced her lab’s investigations in the field of atherosclerosis.