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Caspase-1-licensed lung epithelial cell pyroptosis drives infiltrating neutrophil necroptosis to dampen immune defense against pulmonary bacterial infection

ABSTRACT: Lower respiratorytractinfections, especially those caused by bacteria, are responsible for a large number of deaths each year and are a leading global health issue. Pulmonary bacterial infection causes a severe host response and cell death, such as pyroptosis and necroptosis. However, its pathogenesis is complicated, and whether these different types of cell death communicate with each other and whether these communications are involved in the process of infection remains unknown. Here, we showed that the global deficiency of caspase-1 can protect against lethal pulmonary E. coli infection by reducing the necroptosis of infiltrated neutrophils, which are key players in immune responses in the lung. Mechanistically, neutrophil necroptosis was not directly triggered in a cell-intrinsic manner by invading bacteria. Activation of caspase-1 led to remarkable pyroptotic death of lung epithelial cells, which facilitated the release of intracellular dsRNA. The dsRNA was subsequently taken up by neutrophils and bound to ZBP1 to trigger neutrophil necroptosis. Moreover, blocking dsRNA or depleting ZBP1 ameliorated the pathophysiological process of pulmonary E. coli infection. Overall, our results demonstrated a paradigm of communication between necroptosis and pyroptosis in different cell types cooperated by microbes and hosts and suggest that therapeutic targeting of the pyroptosis or necroptosis pathway may prevent pulmonary bacterial infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE242879 | GEO | 2025/06/05

REPOSITORIES: GEO

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Project description:COVID-19 has rapidly circulated around the globe and caused significant morbidity and mortality. The disease is characterized by excessive production of pro-inflammatory cytokines and acute lung damage and patient mortality. Although initial cytokine cascades may be beneficial to the host for clearing the virus, enhanced production of pro-inflammatory cytokines and increasing levels in the systemic circulation, referred to as cytokine storm, can promote tissue damage by inducing inflammatory cell death in both infected and bystander cells. Of the multiple inflammatory cytokines produced by innate immune cells during SARS-CoV-2 infection, we found that the combination of TNF-α and IFN-γ specifically induced cell death characterized by GSDME¬–mediated pyroptosis, caspase-8–mediated apoptosis, and MLKL–mediated necroptosis. Cells deficient in both RIPK3 and caspase-8 or RIPK3 and FADD were resistant to this cell death. However, deletion of pyroptosis, apoptosis, or necroptosis individually was not sufficient to protect against cell death. Mechanistically, the STAT1/IRF1 axis activated by TNF-α and IFN-γ co-treatment induced iNOS for the production of nitric oxide. Pharmacological and genetic deletion of this pathway inhibited pyroptosis, apoptosis, and necroptosis in macrophages. Moreover, inhibition of inflammatory cell death protected mice from TNF-α and IFN-γ–induced lethal cytokine shock that mirrors the pathological symptoms of COVID-19. To determine the physiological relevance of protection, we neutralized both TNF-α and IFN-γ in multiple disease models associated with cytokine storm and found that this treatment provided substantial protection against not only SARS-CoV-2 infection, but also sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock models. Collectively, our findings reveal that blocking the COVID-19 cytokine-mediated inflammatory cell death signaling pathway identified in this study may benefit patients with COVID-19 or other cytokine storm-driven syndromes by limiting inflammation and tissue damage. Additionally, these results open new avenues for the treatment of other infectious and autoinflammatory diseases and cancer where TNF-α and IFN-γ synergism play key pathological roles.

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Caspase-1-licensed lung epithelial cell pyroptosis drives infiltrating neutrophil necroptosis to dampen immune defense against pulmonary bacterial infection

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