2. Academic Validation
  3. Gasdermin D-mediated metabolic crosstalk promotes tissue repair

Gasdermin D-mediated metabolic crosstalk promotes tissue repair

  • Nature. 2024 Sep 11. doi: 10.1038/s41586-024-08022-7.
Zhexu Chi # 1 2 3,  Sheng Chen # 4 5,  Dehang Yang # 6 7,  Wenyu Cui 8,  Yang Lu 6,  Zhen Wang 6,  Mobai Li 6,  Weiwei Yu 4 5,  Jian Zhang 7,  Yu Jiang 6,  Ruya Sun 6,  Qianzhou Yu 6,  Tianyi Hu 6,  Xiaoyang Lu 6,  Qiqi Deng 6,  Yidong Yang 6,  Tianming Zhao 6,  Mengfei Chang 6,  Yuying Li 9,  Xue Zhang 10,  Min Shang 11,  Qian Xiao 4 5,  Kefeng Ding 4 5,  Di Wang 12 13
Affiliations

Affiliations

  • 1 Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. ralf@zju.edu.cn.
  • 2 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China. ralf@zju.edu.cn.
  • 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. ralf@zju.edu.cn.
  • 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.
  • 5 Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China.
  • 6 Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.
  • 8 Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 9 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.
  • 10 Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China.
  • 11 Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 12 Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. diwang@zju.edu.cn.
  • 13 Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China. diwang@zju.edu.cn.
  • # Contributed equally.
PMID: 39260418 DOI: 10.1038/s41586-024-08022-7
Abstract

The establishment of an early pro-regenerative niche is crucial for tissue regeneration1,2. Gasdermin D (GSDMD)-dependent Pyroptosis accounts for the release of inflammatory cytokines upon various insults3-5. However, little is known about its role in tissue regeneration followed by homeostatic maintenance. Here we show that macrophage GSDMD deficiency delays tissue recovery but has little effect on the local inflammatory milieu or the lytic Pyroptosis process. Profiling of the metabolite secretome of hyperactivated macrophages revealed a non-canonical metabolite-secreting function of GSDMD. We further identified 11,12-epoxyeicosatrienoic acid (11,12-EET) as a bioactive, pro-healing oxylipin that is secreted from hyperactive macrophages in a GSDMD-dependent manner. Accumulation of 11,12-EET by direct supplementation or deletion of Ephx2, which encodes a 11,12-EET-hydrolytic Enzyme, accelerated muscle regeneration. We further demonstrated that EPHX2 accumulated within aged muscle, and that consecutive 11,12-EET treatment rejuvenated aged muscle. Mechanistically, 11,12-EET amplifies Fibroblast Growth Factor signalling by modulating liquid-liquid phase separation of fibroblast growth factors, thereby boosting the activation and proliferation of muscle stem cells. These data depict a GSDMD-guided metabolite crosstalk between macrophages and muscle stem cells that governs the repair process, which offers insights with therapeutic implications for the regeneration of injured or aged tissues.

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