PDF(Pubmed)
Abstract：
Thromboembolic complications and excessive inflammation are frequent in severe COVID-19, potentially leading to long COVID. In non-COVID studies, we and others demonstrated that circulating Reelin promotes leukocyte infiltration and thrombosis. Thus, we hypothesized that Reelin participates in endothelial dysfunction and hyperinflammation during COVID-19. We showed that Reelin was increased in COVID-19 patients and correlated with the disease activity. In the severe COVID-19 group, we observed a hyperinflammatory state, as judged by increased concentration of cytokines (IL-1α, IL-4, IL-6, IL-10 and IL-17A), chemokines (IP-10 and MIP-1β), and adhesion markers (E-selectin and ICAM-1). Reelin level was correlated with IL-1α, IL-4, IP-10, MIP-1β, and ICAM-1, suggesting a specific role for Reelin in COVID-19 progression. Furthermore, Reelin and all of the inflammatory markers aforementioned returned to normal in a long COVID cohort, showing that the hyperinflammatory state was resolved. Finally, we tested Reelin inhibition with the anti-Reelin antibody CR-50 in hACE2 transgenic mice infected with SARS-CoV-2. CR-50 prophylactic treatment decreased mortality and disease severity in this model. These results demonstrate a direct proinflammatory function for Reelin in COVID-19 and identify it as a drug target. This work opens translational clinical applications in severe SARS-CoV-2 infection and beyond in auto-inflammatory diseases.
摘要：
血栓栓塞并发症和过度炎症在严重的COVID-19中很常见，可能导致长期COVID。在非COVID研究中，我们和其他人证明循环Reelin促进白细胞浸润和血栓形成。因此，我们假设Reelin参与COVID-19期间的内皮功能障碍和过度炎症。我们发现Reelin在COVID-19患者中增加，并与疾病活动相关。在严重的COVID-19组中，我们观察到了高炎症状态，根据细胞因子浓度的增加(IL-1α，IL-4，IL-6，IL-10和IL-17A），趋化因子（IP-10和MIP-1β），和粘附标志物(E-选择素和ICAM-1)。Reelin水平与IL-1α相关,IL-4，IP-10，MIP-1β，和ICAM-1，表明Reelin在COVID-19进展中的特定作用。此外，Reelin和上述所有炎症标志物在一个长的COVID队列中恢复正常，表明高炎性状态得到解决。最后,我们在感染SARS-CoV-2的hACE2转基因小鼠中测试了抗Reelin抗体CR-50对Reelin的抑制作用。在该模型中,CR-50预防性治疗降低了死亡率和疾病严重程度。这些结果表明Reelin在COVID-19中具有直接的促炎功能，并将其鉴定为药物靶标。这项工作为严重的SARS-CoV-2感染以及自身炎性疾病的转化临床应用开辟了道路。
