PGC1α alleviates M1 macrophage polarization through dual regulation of succinate metabolism and TRAF5 expression to mitigate TLR4/NF-κB-driven inflammatory cascades and myocardial ischemia/reperfusion injury

Inflamm Res. 2025 Nov 6;74(1):156. doi: 10.1007/s00011-025-02109-1.

Abstract

Objective: This study investigates the dual regulatory role of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) in macrophage polarization and its therapeutic potential for mitigating myocardial ischemia/reperfusion injury (MI/RI).

Methods: By integrating in vivo murine myocardial MI/RI models with macrophage-specific genetic manipulation and multi-omics analyses, including transcriptomics, proteomics, and energy metabolomics, we comprehensively investigated the cardio-protective effects, immune regulation, and potential mechanism of PGC1α. Mechanistic validations were performed using macrophage hypoxia/reoxygenation models combined with gain- and loss-of-function experiments to elucidate the molecular interactions within the PGC1α-mediated signaling network.

Results: PGC1α emerged as a potential regulator of macrophage polarization through coordinated metabolic and protein regulation in MI/RI. It suppresses TLR4/NF-κB-driven inflammation via two prominent parallel pathways: (1) Metabolic control through SUCLG1/succinyl-CoA synthetase-mediated succinate generation; (2) negatively regulates protein by TRAF5 mRNA expression inhibition. This dual-axis regulation effectively dampens M1 macrophage polarization and pro-inflammatory cytokine storms. Furthermore, macrophage-specific PGC1α activation demonstrated cardio-protective effects by preserving cardiac function and reducing cardiomyocyte apoptosis.

Conclusion: Our findings established PGC1α as a potential regulator of macrophage polarization in MI/RI, bridging mitochondrial energy metabolism and protein expression with immune responses. The PGC1α-SUCLG1/succinate axis and PGC1α-TRAF5 axis unveil therapeutic targets and potential mechanisms for modulating inflammation in MI/RI. Future studies should focus on translating these mechanisms into clinical interventions through pharmacological PGC1α activation.

Keywords: Immunometabolic crosstalk; M1 macrophage polarization; Myocardial ischemia–reperfusion injury; PGC1α; TLR4/NF-κB signaling.

MeSH terms

  • Animals
  • Inflammation / immunology
  • Inflammation / metabolism
  • Macrophages* / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Reperfusion Injury* / immunology
  • Myocardial Reperfusion Injury* / metabolism
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha* / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha* / metabolism
  • Signal Transduction
  • Succinic Acid* / metabolism
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism

Substances

  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Toll-Like Receptor 4
  • NF-kappa B
  • Succinic Acid
  • Ppargc1a protein, mouse
  • Tlr4 protein, mouse