Gasdermin D-mediated metabolic crosstalk promotes tissue repair

Zhexu Chi (), Sheng Chen, Dehang Yang, Wenyu Cui, Yang Lu, Zhen Wang, Mobai Li, Weiwei Yu, Jian Zhang, Yu Jiang, Ruya Sun, Qianzhou Yu, Tianyi Hu, Xiaoyang Lu, Qiqi Deng, Yidong Yang, Tianming Zhao, Mengfei Chang, Yuying Li, Xue Zhang, Min Shang, Qian Xiao, Kefeng Ding and Di Wang ()
Additional contact information
Zhexu Chi: Zhejiang University School of Medicine
Sheng Chen: Zhejiang University School of Medicine
Dehang Yang: Zhejiang University School of Medicine
Wenyu Cui: Zhejiang University School of Medicine
Yang Lu: Zhejiang University School of Medicine
Zhen Wang: Zhejiang University School of Medicine
Mobai Li: Zhejiang University School of Medicine
Weiwei Yu: Zhejiang University School of Medicine
Jian Zhang: Zhejiang University Medical Center
Yu Jiang: Zhejiang University School of Medicine
Ruya Sun: Zhejiang University School of Medicine
Qianzhou Yu: Zhejiang University School of Medicine
Tianyi Hu: Zhejiang University School of Medicine
Xiaoyang Lu: Zhejiang University School of Medicine
Qiqi Deng: Zhejiang University School of Medicine
Yidong Yang: Zhejiang University School of Medicine
Tianming Zhao: Zhejiang University School of Medicine
Mengfei Chang: Zhejiang University School of Medicine
Yuying Li: University of Chinese Academy of Sciences
Xue Zhang: Zhejiang University School of Medicine
Min Shang: Zhejiang University School of Medicine
Qian Xiao: Zhejiang University School of Medicine
Kefeng Ding: Zhejiang University School of Medicine
Di Wang: Zhejiang University School of Medicine

Nature, 2024, vol. 634, issue 8036, 1168-1177

Abstract: 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.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-08022-7 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:634:y:2024:i:8036:d:10.1038_s41586-024-08022-7

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-08022-7

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().