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

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. To exam the difference gene expression of casp1-/- and WT mice lung alveolar neutrophils during E.coli pneumonia, we collected the BALF neutrophils from disease mice and performed gene expression profiling analysis from RNA-seq date acquired from these neutrophils.