Apelin-13 alleviates post-infarction injury by modulating macrophage inflammation via APJ-dependent inhibition of NLRP3-mediated pyroptosis
- Int Immunopharmacol. 2026 Jul 1:180:116666. doi: 10.1016/j.intimp.2026.116666.
- 1. Air Force Medical Center, Fourth Military Medical University, 30 Fucheng Road, Haidian District, Beijing 100142, China.
- 2. Department of Emergency Medicine, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, Shaanxi Province, China.
- 3. Xijing Hospital, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, Shaanxi Province, China.
- 4. Department of Emergency Medicine, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, Shaanxi Province, China. Electronic address: [email protected].
- 5. Air Force Medical Center, Fourth Military Medical University, 30 Fucheng Road, Haidian District, Beijing 100142, China. Electronic address: [email protected].
Background: Sustained macrophage-driven inflammation critically exacerbates post-infarction myocardial injury and remodeling. While Apelin-13 (A13) is known for its cardiovascular benefits, its direct immunomodulatory role on Macrophages after Myocardial Infarction (MI) remains undefined.
Methods: We established a mouse MI model and a hypoxia/Hypoglycemia (Hyp) model with macrophage-cardiomyocyte Transwell co-culture. A13 was administered systemically in vivo and used for macrophage preconditioning in vitro. For functional validation, A13-modulated Macrophages were transplanted intramyocardially into infarcted Hearts. Comprehensive molecular profiling encompassed RNA Sequencing, western blotting, flow cytometry, and cytokine ELISA. Specific inhibitors were applied to dissect the APJ/NLRP3 axis.
Results: A13 treatment significantly improved cardiac function, attenuated adverse remodeling, and suppressed pro-inflammatory cytokine release. Importantly, intramyocardial transplantation of A13-modulated Macrophages directly mitigated the injury-aggravating effects of stressed Macrophages, as evidenced by improved cardiac function, reduced fibrosis and inflammatory infiltration, and attenuated oxidative damage. Transcriptomic analysis identified reversal of Hyp-induced pro-inflammatory signatures, with marked enrichment in the NOD-like Receptor pathway. A13 acted through the APJ receptor to inhibit NLRP3 inflammasome assembly, Caspase-1 activation, GSDMD cleavage, and IL-1β maturation, thereby suppressing macrophage Pyroptosis.
Conclusions: Our findings uncover a novel mechanism by which A13 alleviates post-MI injury through APJ-dependent inhibition of NLRP3-mediated Pyroptosis in Macrophages, providing a promising immunomodulatory axis for therapeutic intervention.