The extracellular cyclophilin A-integrin β2 complex as a therapeutic target of 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

doi:10.1016/j.ymthe.2024.03.008

The extracellular cyclophilin A-integrin β2 complex as a therapeutic target of viral pneumonia

Mol Ther. 2024 May 1;32(5):1510-1525. doi: 10.1016/j.ymthe.2024.03.008. Epub 2024 Mar 7.

Authors

Xiaoyuan Bai¹, Wenxian Yang¹, Yuna Zhao², Tongtong Cao³, Runshan Lin⁴, Pengtao Jiao⁵, Heqiao Li¹, Huizi Li⁴, Jie Min⁴, Xiaoxiao Jia⁵, He Zhang⁶, Wenhui Fan⁵, Xiaojuan Jia⁷, Yuhai Bi⁸, Wenjun Liu⁹, Lei Sun¹⁰

Affiliations

¹ Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518107, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
² CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources & Laboratory of Animal Infectious Diseases, College of Animal Sciences and Veterinary Medicine, Guangxi University, Nanning 530004, Guangxi, China.
³ Department of Traditional Chinese Medicine, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
⁴ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China.
⁵ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
⁶ Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518107, China.
⁷ The Biological Safety level-3 (BSL-3) Laboratory of Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
⁸ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China; The Biological Safety level-3 (BSL-3) Laboratory of Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
⁹ Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518107, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources & Laboratory of Animal Infectious Diseases, College of Animal Sciences and Veterinary Medicine, Guangxi University, Nanning 530004, Guangxi, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China.
¹⁰ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].

PMID: 38454605
PMCID: PMC11081868 (available on 2025-05-01)
DOI: 10.1016/j.ymthe.2024.03.008

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.

Keywords: cyclophilin A; cytokine; integrin β2; leukocyte trafficking; viral pneumonia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Monoclonal / pharmacology
CD18 Antigens / metabolism
COVID-19* / immunology
COVID-19* / metabolism
COVID-19* / virology
Cyclophilin A* / metabolism
Cytokines / metabolism
Disease Models, Animal
Humans
Influenza A virus
Mice
Pneumonia, Viral / drug therapy
Pneumonia, Viral / immunology
Pneumonia, Viral / metabolism
Pneumonia, Viral / virology
SARS-CoV-2
Signal Transduction

Substances

Cyclophilin A
CD18 Antigens
Cytokines
Antibodies, Monoclonal