Abstract
Sepsis-induced acute lung injury (ALI) involves a complex interplay between immune cells and the pulmonary endothelium. However, the molecular regulators that coordinate this interaction remain poorly defined. In a murine sepsis model, we identified a subset of lung-resident macrophages characterized by robust IL-1β expression as pivotal contributors to lung damage. Single-cell RNA sequencing (scRNA-seq) delineated a distinct IL-1β⁺ macrophage population with pronounced pro-inflammatory transcriptional features and enhanced endothelial communication. These macrophages exhibited intensified ligand–receptor interactions with pulmonary endothelial cells, corresponding with elevated vascular leakage and histopathological evidence of injury. Immunoassays, Western blotting, and histopathology confirmed IL-1β upregulation during lung injury. Furthermore, metabolomics and in vitro co-culture experiments demonstrated that IL-1β impairs endothelial integrity and modulates metabolic activity. This study reveals a novel immune-metabolic axis whereby IL-1β+ macrophages orchestrate endothelial dysfunction and tissue injury in sepsis. Our findings highlight IL-1β as a potential therapeutic target for mitigating ALI in septic patients.
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The datasets generated and/or analyzed during the current study are available in the manuscript and supplementary materials. Full and uncropped Western blot images are available in the supplementary materials. Further requests are available from the corresponding author on reasonable request.
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TL and YD performed the experiments, analyzed the data, and drafted the manuscript. DL and BF assisted with data interpretation and figure preparation. YT and HF conceived and supervised the study, secured funding, and revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.
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All animal experiments were approved by the Animal Ethics Committee of The First Affiliated Hospital, Jiangxi Medical College, Nanchang University (CDYFY-IACUC-202505GR047).
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Dong, Y., Li, T., Fang, B. et al. IL-1β+ lung-resident macrophages mediate endothelial dysfunction and acute lung injury in sepsis through immune-metabolic crosstalk. Cell Death Discov. (2025). https://doi.org/10.1038/s41420-025-02868-0
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DOI: https://doi.org/10.1038/s41420-025-02868-0
