PDF(Pubmed)
Abstract：
The acute respiratory virus infection can induce uncontrolled inflammatory responses, such as cytokine storm and viral pneumonia, which are the major causes of death in clinical cases. Cyclophilin A (CypA) is mainly distributed in the cytoplasm of resting cells and released into the extracellular space in response to inflammatory stimuli. Extracellular CypA (eCypA) is upregulated and promotes inflammatory response in severe COVID-19 patients. However, how eCypA promotes virus-induced inflammatory response remains elusive. Here, we observe that eCypA is induced by influenza A and B viruses and SARS-CoV-2 in cells, mice, or patients. Anti-CypA mAb reduces pro-inflammatory cytokines production, leukocytes infiltration, and lung injury in virus-infected mice. Mechanistically, eCypA binding to integrin β2 triggers integrin activation, thereby facilitating leukocyte trafficking and cytokines production via the focal adhesion kinase (FAK)/GTPase and FAK/ERK/P65 pathways, respectively. These functions are suppressed by the anti-CypA mAb that specifically blocks eCypA-integrin β2 interaction. Overall, our findings reveal that eCypA-integrin β2 signaling mediates virus-induced inflammatory response, indicating that eCypA is a potential target for antibody therapy against viral pneumonia.
摘要：
急性呼吸道病毒感染可引起不受控制的炎症反应，如细胞因子风暴和病毒性肺炎，这是临床病例中死亡的主要原因。亲环蛋白A(CypA)主要分布在静息细胞的细胞质中,并响应炎症刺激而释放到细胞外空间。细胞外CypA（eCypA）上调并促进严重COVID-19患者的炎症反应。然而,eCypA如何促进病毒诱导的炎症反应仍然难以捉摸。这里,我们观察到eCypA是由甲型和乙型流感病毒以及细胞中的SARS-CoV-2诱导的，老鼠,或患者。抗CypAmAb减少促炎细胞因子的产生，白细胞浸润,和病毒感染小鼠的肺损伤。机械上,eCypA与整合素β2结合触发整合素激活，从而分别通过FAK/GTP酶和FAK/ERK/P65途径促进白细胞运输和细胞因子产生。这些功能被特异性阻断eCypA-整联蛋白β2相互作用的抗CypAmAb抑制。总的来说,我们的研究结果表明，eCypA-整合素β2信号介导病毒诱导的炎症反应，这表明eCypA是针对病毒性肺炎的抗体治疗的潜在靶标。
