Journal Article

Caspase-1-licensed pyroptosis drives dsRNA-mediated necroptosis and dampens host defense against bacterial pneumonia

Luo, Qinyu, Yang, Shiyue, Shu, Qiang, Pan, Yihang, Zhang, Yan, Wu, Zehua, Shen, Lihua, Chen, Qixing

2025

Overview

Bacterial lung infections cause severe host responses. Here, we showed that global deficiency of caspase-1 can protect against lethal pulmonary Escherichia 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 but was triggered by bacteria-stimulated pyroptotic epithelial cell supernatants in vitro . In validation experiments, chimeric mice with nonhematopoietic caspase-1 or GSDMD knockout were protected from lung E. coli infection and exhibited decreased neutrophil death. Nonhematopoietic pyroptosis facilitates the release of dsRNAs and contributes to neutrophil ZBP1-related necroptosis. Moreover, blocking dsRNA or depleting ZBP1 ameliorated the pathophysiological process of pulmonary E. coli infection. Overall, our results demonstrate a paradigm of communication between necroptosis and pyroptosis in different cell types in cooperation with microbes and hosts and suggest that therapeutic targeting of the pyroptosis or necroptosis pathway may prevent pulmonary bacterial infection.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Apoptosis / Bacteria / Bacterial diseases / Bacterial infections / Bacterial pneumonia / Biology and Life Sciences / Bronchopulmonary infection / Caspase 1 - genetics / Caspase 1 - immunology / Caspase 1 - metabolism / Caspase-1 / Cell death / Development and progression / Double-stranded RNA / Drug resistance / E coli / Epithelial cells / Epithelium / Escherichia coli / Escherichia coli Infections - immunology / Escherichia coli Infections - pathology / Gasdermins / Genetic aspects / Global health / Gram-positive bacteria / Health aspects / Host-bacteria relationships / Immune response / Infectious diseases / Kinases / Leukocytes / Leukocytes (neutrophilic) / Lungs / Medicine and Health Sciences / Mice / Mice, Inbred C57BL / Mice, Knockout / Mortality / Necroptosis / Necroptosis - immunology / Neutrophils / Neutrophils - immunology / Neutrophils - pathology / Pathogenesis / Pathogens / Phosphate-Binding Proteins / Physiological aspects / Pneumonia / Pneumonia, Bacterial - immunology / Pneumonia, Bacterial - pathology / Proteins / Pyroptosis / Pyroptosis - immunology / Recruitment / Research and Analysis Methods / RNA-Binding Proteins / Streptococcus infections / Therapeutic targets