GSDME–IL-18 pyroptotic axis prevents myosteatosis by expanding tissue-resident macrophages to promote muscle regeneration
Qi Cao, Jian Liu, Gang Huang, Su-Yuan Wang, Guo-Dong Lu, Yong Huang, Yi-Ting Chen, Zhen Zhang, Jiang-Tao Fu, Si-Jia Sun, Xiao-Fei Chen, Chunlin Zhuang, Chunquan Sheng, Fu-Ming Shen, Dong-Jie Li, Pei Wang
Qi Cao, Jian Liu, Gang Huang, Su-Yuan Wang, Guo-Dong Lu, Yong Huang, Yi-Ting Chen, Zhen Zhang, Jiang-Tao Fu, Si-Jia Sun, Xiao-Fei Chen, Chunlin Zhuang, Chunquan Sheng, Fu-Ming Shen, Dong-Jie Li, Pei Wang
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Research Article Immunology Inflammation Metabolism

GSDME–IL-18 pyroptotic axis prevents myosteatosis by expanding tissue-resident macrophages to promote muscle regeneration

Abstract

Metabolic–inflammatory crosstalk orchestrates muscle repair. Although pyroptosis typically aggravates sterile injury, we demonstrated that GSDME-dependent pyroptotic signaling associated with recruited myeloid cells paradoxically supported regeneration. GSDME expression was induced in postsurgical human muscle injury and murine damage models. Gsdme deficiency delayed functional recovery and exacerbated injury-induced myosteatosis, a pathological form of intramuscular ectopic fat deposition. Time-series and scRNA-seq analyses revealed that GSDME loss shifted the transcriptional program from oxidative metabolism to lipid storage and adipogenesis. Lipidomics confirmed aberrant accumulation of triacylglycerols (TAGs) and sphingolipids in Gsdme-deficient muscle. Single-cell profiling further identified divergent fibro-adipogenic progenitor (FAP) states skewed toward adipogenesis, accompanied by impaired expansion of restorative Lyve1+Cd163+Txnip+ tissue-resident macrophages (TRMs), as validated by multiplex flow cytometry. Blocking CCR2-dependent monocyte recruitment produced regenerative defects comparable with those caused by Gsdme deficiency. Myeloid-specific Gsdme reintroduction rescued TRM expansion and function and curbed FAP adipogenic reprogramming, whereas FAP-specific expression proved ineffective. Mechanistically, IL-18 downstream of GSDME-dependent signaling engaged KLF4/JUN signaling in TRMs, sustaining their reparative and lipid-clearing capacity. This GSDME–IL-18–TRM axis was compromised in aged muscle, yet exogenous IL-18 reversed myosteatosis and accelerated regeneration. Together, these findings suggest that GSDME-dependent pyroptotic signaling can act as a metabolic checkpoint that sustains TRM-driven lipid homeostasis to support muscle regeneration.

Authors

Qi Cao, Jian Liu, Gang Huang, Su-Yuan Wang, Guo-Dong Lu, Yong Huang, Yi-Ting Chen, Zhen Zhang, Jiang-Tao Fu, Si-Jia Sun, Xiao-Fei Chen, Chunlin Zhuang, Chunquan Sheng, Fu-Ming Shen, Dong-Jie Li, Pei Wang

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Figure 3

Lipidomics reveals increased intramuscular TAG enrichment in the absence of Gsdme.

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Lipidomics reveals increased intramuscular TAG enrichment in the absence...
(A) Experimental design for untargeted lipidomics analysis using ultraperformance liquid chromatography–mass spectrometry in injured muscle of WT and KO mice at D14. (B) OPLS score plots assessing robustness of the mass spectrometry–based lipidomics model. (C) Lipid species identified in injured muscle of WT and KO mice: TAGs, PC, and phosphatidylethanolamine (PE). (D) Volcano plot showing the upregulated and downregulated lipid species in KO mouse muscle versus WT muscle. (E) KEGG pathway analysis of lipid-associated functions based on differential lipid species between WT and KO injured muscle; upregulated species are in red, and downregulated species are in blue. (F) Heatmap of differential lipid species in injured skeletal muscle from WT and KO mice. (G) Levels of saturated and unsaturated fatty acids in TAG species. (H) TAG levels of long-chain fatty acids with 47, 48, 49, 50, and 51 carbon atoms. Data are presented as mean ± SEM and were analyzed by unpaired 2-tailed Student’s t test. *P < 0.05, **P < 0.01.