1. Academic Validation
  2. Synergism of TNF-α and IFN-β triggers human airway epithelial cells death by apoptosis and pyroptosis

Synergism of TNF-α and IFN-β triggers human airway epithelial cells death by apoptosis and pyroptosis

  • Mol Immunol. 2022 Dec 9;153:160-169. doi: 10.1016/j.molimm.2022.12.002.
Rui Sun 1 Kaimin Jiang 1 Chengyue Zeng 1 Rui Zhu 2 Hanyu Chu 1 Huiyong Liu 1 Jingchun Du 3
Affiliations

Affiliations

  • 1 Department of Clinical Immunology, Kingmed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, Guangdong 510182, China.
  • 2 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China.
  • 3 Department of Clinical Immunology, Kingmed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, Guangdong 510182, China; Guangzhou Key Laboratory of Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, Guangzhou Medical University, Guangzhou, Guangdong 510182, China. Electronic address: hnxydjc@gzhmu.edu.cn.
Abstract

Cytokine release syndrome, also called cytokine storm, could cause lung tissue damage, acute respiratory distress syndrome (ARDS) and even death during SARS-CoV-2 Infection. However, the underlying mechanisms of cytokine storm still remain unknown. Among these cytokines, the function of TNF-α and type I IFNs especially deserved further investigation. Here, we first found that TNF-α and IFN-β synergistically induced human airway epithelial cells BEAS-2B death. Mechanistically, the combination of TNF-α and IFN-β led to the activation of Caspase-8 and Caspase-3, which initiated BEAS-2B Apoptosis. The activated Caspase-8 and Caspase-3 could further induce the cleavage and activation of gasdermin D (GSDMD) and gasdermin E (GSDME), which finally resulted in pro-inflammatory Pyroptosis. The knock-down of Caspase-8 and Caspase-3 could effectively block the activation of GSDMD and GSDME, and then the death of BEAS-2B induced by TNF-α and IFN-β. In addition, pan-caspase inhibitor Z-VAD-FMK (ZVAD) and necrosulfonamide (NSA) could inhibit BEAS-2B death induced by TNF-α and IFN-β. Overall, our work revealed one possible mechanism that cytokine storm causes airway epithelial cells (AECs) damage and ARDS. These results indicated that blocking TNF-α and IFN-β-mediated AECs death may be a potential target to treat related viral infectious diseases, such as COVID-19.

Keywords

Airway epithelial cells; Apoptosis; IFN-β; Pyroptosis; TNF-α.

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