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

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-alpha and type I IFNs especially deserved further investigation. Here, we first found that TNF-alpha and IFN-beta synergistically induced human airway epithelial cells BEAS-2B death. Mechanistically, the combination of TNF-alpha and IFN-beta 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-alpha and IFN-beta. In addition, pan-caspase inhibitor Z-VAD-FMK (ZVAD) and necrosulfonamide (NSA) could inhibit BEAS-2B death induced by TNF-alpha and IFN-beta. Overall, our work revealed one possible mechanism that cytokine storm causes airway epithelial cells (AECs) damage and ARDS. These results indicated that blocking TNF-alpha and IFN-beta-mediated AECs death may be a potential target to treat related viral infectious diseases, such as COVID-19.