Abstract
There are no specific treatments for Sepsis-associated acute kidney injury (AKI). We previously reported that Il-17a-knockout mice had dramatically improved survival after cecal ligation and puncture (CLP). Neutrophil extracellular traps (NETs) induce IL-17A, which causes harm in some diseases, but this pathway is poorly understood in sepsis. We found that knockout of Pad4 (Peptidyl Arginine Deiminase 4), an enzyme essential for NET formation, improved survival and AKI, and suppressed neutrophil infiltration into remote organs, involving a peritoneal IL-17A/distant organ CXCL-1/CXCL-2 pathway after CLP. NETs were detected in the peritoneal cavity, and not in plasma or distant organs. Adoptive transfer of peritoneal WT neutrophils restored the IL-17A/CXCL-1/CXCL-2 pathway in Pad4KO mice, leading to neutrophil infiltration and damage to remote organs. These results revealed a pathway from peritoneal NET formation to remote organ injury/inflammation via production of IL-17A at the infectious site and distant organ CXCL-1/CXCL-2. While NETs promoted intraperitoneal IL-17A production, we also showed that conversely, peritoneal IL-17A or CXCL-1/CXCL-2 promoted intraperitoneal NET formation after CLP. This peritoneal vicious cycle that includes NET formation, IL-17A, CXCL-1/CXCL-2 that may amplify sepsis-associated organ injury. Breaking this vicious cycle by inhibiting NET formation and/or IL-17A might be a promising therapeutic target for sepsis treatment.
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Acknowledgements
This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) within the National Institutes of Health (NIH). The contributions of the NIH authors are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. We thank Jeff M. Reece (Advanced Light Microscopy & Image Analysis Core, NIDDK, NIH), Pradeep Dagur (Flow Cytometry Core at the National Heart, Lung, and Blood Institute, NIH), and Teruhiko Yoshida (NIDDK, NIH) for technical support.
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Open access funding provided by the National Institutes of Health. This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) within the National Institutes of Health (NIH). The contributions of the NIH authors are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. Open access funding provided by the National Institutes of Health
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Y.N., N.H., P.Y., and R.S. conceived and designed research; Y.N., D.G., N.H., and X.H. performed experiments; Y.N., D.G., and N.H. analyzed data; Y.N., P.Y., and R.S. interpreted results of experiments; Y.N., P.Y., and R.S. prepared figures; Y.N., D.G., N.H., P.Y., and R.S. drafted manuscript; Y.N., D.G., N.H., P.Y., and R.S. edited and revised manuscript; Y.N., D.G., N.H., X.H., P.Y., and R.S. approved final version of manuscript.
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Naito, Y., Goto, D., Hayase, N. et al. Peritoneal neutrophil extracellular traps contribute to septic AKI via peritoneal IL-17A and distant organ CXCL-1/ CXCL-2 pathway in abdominal sepsis. Sci Rep (2026). https://doi.org/10.1038/s41598-025-34770-1
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DOI: https://doi.org/10.1038/s41598-025-34770-1
