Zhang Lifang, Zhang Qingchao, Chang Jiahui, Zhou Yunyi, Wang Wei, Wang Xiliang, Jiang Chengyu, Zhang Yanli
State 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 College, Beijing, 100005, China.
State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.
BMC Infect Dis. 2025 Jan 20;25(1):83. doi: 10.1186/s12879-025-10490-9.
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 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 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.
流感相关急性肺损伤是一种危及生命的病症，主要由流感病毒的不受控制复制和强烈的促炎反应引起。 Cereblon（CRBN）是一种因其在泛素 - 蛋白酶体系统中的作用以及作为药物沙利度胺的靶点而闻名的蛋白质。然而，CRBN在流感病毒感染中的功能仍知之甚少。在本研究中，我们研究了CRBN对A/波多黎各/8/34（PR8）流感病毒诱导的肺损伤的影响及其作为治疗靶点的潜力。在体外敲低CRBN可显著降低PR8诱导的细胞死亡。使用Sftpc-Cre; Crbn肺特异性Crbn基因敲除小鼠，我们证明Crbn缺陷显著降低了PR8感染小鼠的死亡率、体重减轻、肺部病理学、水肿和病毒载量。PR8感染的Sftpc-Cre; Crbn小鼠肺部炎症细胞浸润明显减少，MAPK途径激活受到抑制，MKK4-JNK-c-JUN信号级联显著下调突出了这一点。总的来说，这些发现表明CRBN通过调节MAPK途径信号在流感诱导的肺损伤发病机制中起关键作用，强调了其作为干预靶点的治疗潜力。
