Lung-specific CRBN knockout attenuates influenza a virus-induced acute lung injury in mice: a potential therapeutic approach
Abstract Influenza-related acute lung injury is a life-threatening condition primarily caused by uncontrolled replication of the influenza virus and intense proinflammatory responses. Cereblon (CRBN) is a protein known for its role in the ubiquitin-proteasome system and as a target of the drug thali...
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2025-01-01
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| Series: | BMC Infectious Diseases |
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| Online Access: | https://doi.org/10.1186/s12879-025-10490-9 |
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| author | Lifang Zhang Qingchao Zhang Jiahui Chang Yunyi Zhou Wei Wang Xiliang Wang Chengyu Jiang Yanli Zhang |
| author_facet | Lifang Zhang Qingchao Zhang Jiahui Chang Yunyi Zhou Wei Wang Xiliang Wang Chengyu Jiang Yanli Zhang |
| author_sort | Lifang Zhang |
| collection | DOAJ |
| description | Abstract Influenza-related acute lung injury is a life-threatening condition primarily caused by uncontrolled replication of the influenza virus and intense proinflammatory responses. Cereblon (CRBN) is a protein known for its role in the ubiquitin-proteasome system and as a target of the drug thalidomide. However, the function of CRBN in influenza virus infection remains poorly understood. In this study, we investigated the impact of CRBN on A/Puerto Rico/8/34 (PR8) influenza virus-induced lung injury and its potential as a therapeutic target. Knocking down CRBN in vitro significantly reduces PR8-induced cell death. Using Sftpc-Cre; Crbn flox/flox lung-specific Crbn knockout mice, we demonstrated that Crbn deficiency significantly decreased mortality, weight loss, lung pathology, edema, and viral load in PR8-infected mice. PR8-infected Sftpc-Cre; Crbn flox/flox mice exhibited a marked reduction in lung inflammatory cell infiltration and suppression of MAPK pathway activation, highlighted by a significant downregulation of the MKK4-JNK-c-JUN signaling cascade. Collectively, these findings indicate that CRBN plays a pivotal role in the pathogenesis of influenza-induced lung injury by modulating MAPK pathway signaling, underscoring its therapeutic potential as a target for intervention. |
| format | Article |
| id | doaj-art-79ae5cd0e9fc4806962992d0bc3b58f1 |
| institution | Kabale University |
| issn | 1471-2334 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | BMC Infectious Diseases |
| spelling | doaj-art-79ae5cd0e9fc4806962992d0bc3b58f12025-01-26T12:17:11ZengBMCBMC Infectious Diseases1471-23342025-01-0125111010.1186/s12879-025-10490-9Lung-specific CRBN knockout attenuates influenza a virus-induced acute lung injury in mice: a potential therapeutic approachLifang Zhang0Qingchao Zhang1Jiahui Chang2Yunyi Zhou3Wei Wang4Xiliang Wang5Chengyu Jiang6Yanli Zhang7State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and EpidemiologyState Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeAbstract Influenza-related acute lung injury is a life-threatening condition primarily caused by uncontrolled replication of the influenza virus and intense proinflammatory responses. Cereblon (CRBN) is a protein known for its role in the ubiquitin-proteasome system and as a target of the drug thalidomide. However, the function of CRBN in influenza virus infection remains poorly understood. In this study, we investigated the impact of CRBN on A/Puerto Rico/8/34 (PR8) influenza virus-induced lung injury and its potential as a therapeutic target. Knocking down CRBN in vitro significantly reduces PR8-induced cell death. Using Sftpc-Cre; Crbn flox/flox lung-specific Crbn knockout mice, we demonstrated that Crbn deficiency significantly decreased mortality, weight loss, lung pathology, edema, and viral load in PR8-infected mice. PR8-infected Sftpc-Cre; Crbn flox/flox mice exhibited a marked reduction in lung inflammatory cell infiltration and suppression of MAPK pathway activation, highlighted by a significant downregulation of the MKK4-JNK-c-JUN signaling cascade. Collectively, these findings indicate that CRBN plays a pivotal role in the pathogenesis of influenza-induced lung injury by modulating MAPK pathway signaling, underscoring its therapeutic potential as a target for intervention.https://doi.org/10.1186/s12879-025-10490-9Influenza a virusCRBNH1N1Acute lung injury |
| spellingShingle | Lifang Zhang Qingchao Zhang Jiahui Chang Yunyi Zhou Wei Wang Xiliang Wang Chengyu Jiang Yanli Zhang Lung-specific CRBN knockout attenuates influenza a virus-induced acute lung injury in mice: a potential therapeutic approach BMC Infectious Diseases Influenza a virus CRBN H1N1 Acute lung injury |
| title | Lung-specific CRBN knockout attenuates influenza a virus-induced acute lung injury in mice: a potential therapeutic approach |
| title_full | Lung-specific CRBN knockout attenuates influenza a virus-induced acute lung injury in mice: a potential therapeutic approach |
| title_fullStr | Lung-specific CRBN knockout attenuates influenza a virus-induced acute lung injury in mice: a potential therapeutic approach |
| title_full_unstemmed | Lung-specific CRBN knockout attenuates influenza a virus-induced acute lung injury in mice: a potential therapeutic approach |
| title_short | Lung-specific CRBN knockout attenuates influenza a virus-induced acute lung injury in mice: a potential therapeutic approach |
| title_sort | lung specific crbn knockout attenuates influenza a virus induced acute lung injury in mice a potential therapeutic approach |
| topic | Influenza a virus CRBN H1N1 Acute lung injury |
| url | https://doi.org/10.1186/s12879-025-10490-9 |
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