Ninjurin-1 mediates cell lysis and detrimental inflammation of PANoptosis during influenza A virus infection

Influenza A virus (IAV) induces ZBP1-mediated PANoptosis, a form of lytic inflammatory cell death characterized by concurrent activation of the pyroptosis, necroptosis and apoptosis pathways. Ninjurin-1 (NINJ1) is a recently identified mediator of plasma membrane rupture but functions diversely in different types of cell death. However, little is known about the role of NINJ1 in IAV-induced PANoptosis and viral pneumonia. Here, we report that IAV infection triggered an increase in the expression of NINJ1, which then oligomerized and mediated cell lysis in infected macrophages. The deficiency of NINJ1 prevented plasma membrane rupture and the release of DAMPs and IL-1β without affecting the progression of cell death. Activation of any single PANoptosis pathway was sufficient to trigger the oligomerization of NINJ1 and robust cell lysis. Accordingly, only when all PANoptosis pathways were concurrently blocked could the oligomerization of NINJ1, cell death, and cell rupture be prevented. Ablation of NINJ1 in vivo also alleviated IAV-induced lung injury and mortality. Furthermore, we revealed an association between NINJ1 upregulation and poor outcomes in patients with COVID-19. Collectively, our findings indicate a pivotal role of NINJ1 in the immunopathology of IAV infection and its potential as a bioindicator of disease severity and prognosis in viral pneumonia and viral sepsis.

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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2025-09-22
DOI
https://doi.org/10.1038/s41392-025-02391-9
Citations
5
Primary Topic
Inflammasome and immune disorders
Type
article
Field-Weighted Citation Impact
4.03
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article

Ninjurin-1 mediates cell lysis and detrimental inflammation of PANoptosis during influenza A virus infection

Xiao Shang, Xuhui Shen, Xiaoyan Deng, Yi Mu et al.
5 citations
Signal Transduction and Targeted Therapy
Inflammasome and immune disorders
4.03
article

Ninjurin-1 mediates cell lysis and detrimental inflammation of PANoptosis during influenza A virus infection

Xiao Shang, Xuhui Shen, Xiaoyan Deng, Yi Mu, Yaxue Liu, Hongping Wu, Chen Lyu, Wei Cheng, Di He, Ying Zheng, Jianhua Ren, Wenting Zuo, Zai Wang, Yitian Xu, Yan Liu, Haibo Li, Zihuan Zhang, Ziyao Li, Weiwei Ge, Bin Cao, Yi-Jiao Huang, Runqing Gu, Hongyu Liu, Zeyi Wang
article en
5 citations

Abstract

Influenza A virus (IAV) induces ZBP1-mediated PANoptosis, a form of lytic inflammatory cell death characterized by concurrent activation of the pyroptosis, necroptosis and apoptosis pathways. Ninjurin-1 (NINJ1) is a recently identified mediator of plasma membrane rupture but functions diversely in different types of cell death. However, little is known about the role of NINJ1 in IAV-induced PANoptosis and viral pneumonia. Here, we report that IAV infection triggered an increase in the expression of NINJ1, which then oligomerized and mediated cell lysis in infected macrophages. The deficiency of NINJ1 prevented plasma membrane rupture and the release of DAMPs and IL-1β without affecting the progression of cell death. Activation of any single PANoptosis pathway was sufficient to trigger the oligomerization of NINJ1 and robust cell lysis. Accordingly, only when all PANoptosis pathways were concurrently blocked could the oligomerization of NINJ1, cell death, and cell rupture be prevented. Ablation of NINJ1 in vivo also alleviated IAV-induced lung injury and mortality. Furthermore, we revealed an association between NINJ1 upregulation and poor outcomes in patients with COVID-19. Collectively, our findings indicate a pivotal role of NINJ1 in the immunopathology of IAV infection and its potential as a bioindicator of disease severity and prognosis in viral pneumonia and viral sepsis.

Signal Transduction and Targeted TherapyVol. 10(1)
Shandong University of Aeronautics (CN), Harbin Medical University (CN), Capital Medical University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), China-Japan Friendship Hospital (CN), National Clinical Research Center for Digestive Diseases (CN), Second Affiliated Hospital of Harbin Medical University (CN), Beijing Friendship Hospital (CN), Huashan Hospital (CN), Center for Life Sciences (CN), Tsinghua University (CN)
Openalex Percentile: Top 6%
Inflammasome and immune disorders
4.03
DOIOpen Access PDFOpenAlex
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