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Gasdermin D-mediated metabolic crosstalk promotes tissue repair

Wang, Di
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Nature ( 2024 ) Cite this article

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Abstract

The establishment of an early pro-regenerative niche is crucial for tissue regeneration 1,2 . Gasdermin D (GSDMD)-dependent pyroptosis accounts for the release of inflammatory cytokines upon various insults 3-5 . However, little is known about its role in tissue regeneration followed by homeostatic maintenance. Here, we show that macrophage GSDMD deficiency delayed tissue recovery, with little impact on the local inflammatory milieu or the lytic pyroptosis process. Metabolite secretome profiling of hyperactivated macrophages unveiled the non-canonical metabolite-secreting function of GSDMD. And we further identified 11,12-epoxyeicosatrienoic acid (11,12-EET) as a bioactive pro-healing oxylipin, secreted from hyperactive macrophages in a GSDMD-dependent manner. Indeed, accumulation of 11,12-EET by direct supplementation or deletion of its hydrolytic enzyme Ephx2 accelerated muscle regeneration. We further demonstrated that the Ephx2 level accumulated within aged muscle. And consecutive 11,12-EET treatment rejuvenated aged muscle. Mechanistically, 11,12-EET amplifies FGF-FGFR signaling by modulating FGF liquid-liquid phase separation, hence boosting the activation and proliferation of muscle stem cells (MuSCs). These data depict a GSDMD-guided metabolite crosstalk between macrophages and MuSCs that governs the repair process, which offers new therapeutic insights for the regeneration of injured or aged tissues.

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Author notes

  1. These authors contributed equally: Zhexu Chi, Sheng Chen, Dehang Yang

Authors and Affiliations

  1. Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Zhexu Chi, Dehang Yang, Yang Lu, Zhen Wang, Mobai Li, Yu Jiang, Ruya Sun, Qianzhou Yu, Tianyi Hu, Xiaoyang Lu, Qiqi Deng, Yidong Yang, Tianming Zhao, Mengfei Chang & Di Wang

  2. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China

    Jian Zhang & Di Wang

  3. Center for Regeneration and Aging Medicine, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Yiwu, China

    Zhexu Chi

  4. Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Sheng Chen, Weiwei Yu, Qian Xiao & Kefeng Ding

  5. Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China

    Sheng Chen, Weiwei Yu, Qian Xiao & Kefeng Ding

  6. Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Wenyu Cui

  7. CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China

    Yuying Li

  8. Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China

    Xue Zhang

  9. Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Min Shang

Authors

  1. Zhexu Chi

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  2. Sheng Chen

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  3. Dehang Yang

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  4. Wenyu Cui

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  5. Yang Lu

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  6. Zhen Wang

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  7. Mobai Li

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  8. Weiwei Yu

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  9. Jian Zhang

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  10. Yu Jiang

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  11. Ruya Sun

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  12. Qianzhou Yu

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  13. Tianyi Hu

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  14. Xiaoyang Lu

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  15. Qiqi Deng

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  16. Yidong Yang

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  17. Tianming Zhao

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  18. Mengfei Chang

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  19. Yuying Li

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  20. Xue Zhang

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  21. Min Shang

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  22. Qian Xiao

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  23. Kefeng Ding

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  24. Di Wang

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Corresponding authors

Correspondence to Zhexu Chi or Di Wang .

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Chi, Z., Chen, S., Yang, D. et al. Gasdermin D-mediated metabolic crosstalk promotes tissue repair. Nature (2024). https://doi.org/10.1038/s41586-024-08022-7

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  • DOI : https://doi.org/10.1038/s41586-024-08022-7

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