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.
Xiaoyuan Bai, Wenxian Yang, Yuna Zhao, Tongtong Cao, Runshan Lin, Pengtao Jiao, Heqiao Li, Huizi Li, Jie Min, Xiaoxiao Jia, He Zhang, Wenhui Fan, Xiaojuan Jia, Yuhai Bi, Wenjun Liu, Lei Sun
The extracellular cyclophilin A-integrin β2 complex
as a therapeutic target of viral pneumonia
Molecular Therapy, Volume 32, Issue 5, 1 May 2024, Pages 1510-1525
