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Gasdermin D-mediated metabolic crosstalk promotes tissue repair.
Chi, Zhexu; Chen, Sheng; Yang, Dehang; Cui, Wenyu; Lu, Yang; Wang, Zhen; Li, Mobai; Yu, Weiwei; Zhang, Jian; Jiang, Yu; Sun, Ruya; Yu, Qianzhou; Hu, Tianyi; Lu, Xiaoyang; Deng, Qiqi; Yang, Yidong; Zhao, Tianming; Chang, Mengfei; Li, Yuying; Zhang, Xue; Shang, Min; Xiao, Qian; Ding, Kefeng; Wang, Di.
Afiliación
  • Chi Z; Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. ralf@zju.edu.cn.
  • Chen S; 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.
  • Yang D; 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.
  • Cui W; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China.
  • Lu Y; Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Wang Z; Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Li M; Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Yu W; Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Zhang J; Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Jiang Y; 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.
  • Sun R; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China.
  • Yu Q; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.
  • Hu T; Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Lu X; Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Deng Q; Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Yang Y; Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Zhao T; Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Chang M; Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Li Y; Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Zhang X; Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Shang M; Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Xiao Q; 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.
  • Ding K; Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China.
  • Wang D; Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Nature ; 2024 Sep 11.
Article en En | MEDLINE | ID: mdl-39260418
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 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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Nature Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Nature Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido