Abstract
Acetaldehyde dehydrogenase 2 (ALDH2) mutations are commonly found in a subgroup of the Asian population. However, the role of ALDH2 in septic acute respiratory distress syndrome (ARDS) remains unknown. Here, we showed that human subjects carrying the ALDH2rs671 mutation were highly susceptible to developing septic ARDS. Intriguingly, ALDH2rs671-ARDS patients showed higher levels of blood cell-free DNA (cfDNA) and myeloperoxidase (MPO)-DNA than ALDH2WT-ARDS patients. To investigate the mechanisms underlying ALDH2 deficiency in the development of septic ARDS, we utilized Aldh2 gene knockout mice and Aldh2rs671 gene knock-in mice. In clinically relevant mouse sepsis models, Aldh2-/- mice and Aldh2rs671 mice exhibited pulmonary and circulating NETosis, a specific process that releases neutrophil extracellular traps (NETs) from neutrophils. Furthermore, we discovered that NETosis strongly promoted endothelial destruction, accelerated vascular leakage, and exacerbated septic ARDS. At the molecular level, ALDH2 increased K48-linked polyubiquitination and degradation of peptidylarginine deiminase 4 (PAD4) to inhibit NETosis, which was achieved by promoting PAD4 binding to the E3 ubiquitin ligase CHIP. Pharmacological administration of the ALDH2-specific activator Alda-1 substantially alleviated septic ARDS by inhibiting NETosis. Together, our data reveal a novel ALDH2-based protective mechanism against septic ARDS, and the activation of ALDH2 may be an effective treatment strategy for sepsis.
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Acknowledgements
This study was supported by the State Key Program of the National Natural Science Foundation of China (82030059), the National Science Fund for Distinguished Young Scholars (82325031), the National Natural Science Regional Innovation Fund Joint Fund Key Support Projects (U23A20485), the National Natural Science Foundation of China (82072144, 82172127), the National Key R&D Program of China (2020YFC1512700, 2020YFC1512705, 2020YFC1512703), the Key R&D Program of Shandong Province (2021ZLGX02, 2021SFGC0503, 2022ZLGX03), the Taishan Pandeng Scholar Program of Shandong Province (tspd20181220), the Taishan Young Scholar Program of Shandong Province (tsqn202211312), the Clinical Research Project of Shandong University (2021SDUCRCC006), and the Interdisciplinary Young Researcher Groups Program of Shandong University (2020QNQT004). Illustrations were made using BioRender.
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Y Chen and JP conceived and designed the experiments. CX and LZ performed most of the experiments with the help of SX, ZW, QH, YL, XW, XZ, QZ, YZ, SH, and QY CX, LZ, SX, ZW, and YB performed the data analysis. Y Cao and JP assisted in revising the draft. CL, JW, and FX provided valuable experimental advice and guidance. All authors have read and approved the final manuscript.
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Xu, C., Zhang, L., Xu, S. et al. Neutrophil ALDH2 is a new therapeutic target for the effective treatment of sepsis-induced ARDS. Cell Mol Immunol 21, 510–526 (2024). https://doi.org/10.1038/s41423-024-01146-w
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DOI: https://doi.org/10.1038/s41423-024-01146-w