IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome
IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome
复制标题
DOI：
10.1073/pnas.2010229117
复制
发表时间：
2020-09-08
影响因子：
11.1
通讯作者：
Kishimoto, Tadamitsu
中科院分区：
文献类型：
--
作者：
Kang, Sujin;Tanaka, Toshio;Kishimoto, Tadamitsu
细胞因子释放综合征（CRS）是一种危及生命的并发症，由对感染的全身炎症反应引起，包括细菌和嵌合抗原受体T细胞治疗。目前还没有临床有效的免疫疗法，对CRS发病机制的分子机制的理解也很有限。我们发现，因败血症、急性呼吸窘迫综合征（ARDS）或烧伤而诊断为CRS的患者表现出共同的表现：四种促炎细胞因子白细胞介素（IL）-6，IL-8，单核细胞趋化蛋白-1（MCP-1）和IL-10以及凝血级联激活剂纤溶酶原激活物抑制剂-1（派-1）的水平显著升高。我们的体外数据表明，内皮IL-6反式信号传导形成了一个炎症回路，用于稳健的IL-6、IL-8和MCP-1产生，并促进派-1产生;此外，人单克隆抗体托珠单抗阻断IL-6信号传导可减弱内皮细胞活化。来自严重COVID-19患者的血浆类似地显示出IL-6、IL-10和MCP-1水平升高，但这些水平不如来自其他原因的CRS患者高。相比之下，COVID-19患者的派-1水平与细菌性脓毒症或ARDS患者一样高度升高。托珠单抗治疗降低了派-1水平，缓解了重症COVID-19患者的危重疾病。我们的研究结果表明，不同水平的细胞因子产生与细菌感染和COVID-19诱导的CRS相关，但这两种CRS类型都通过IL-6反式信号传导伴有内皮病变。因此，本研究强调了IL-6信号在细菌感染和COVID-19期间内皮功能障碍中的关键作用。
Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.