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

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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