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Rapamycin preserves cardiac function in autoimmune myocarditis by reprogramming Cxcl9+ macrophages via the
Yan Zhuang1, Yongcui Yan1, Zheng Wen1
1Division of Cardiology and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Insights
Rapamycin treats autoimmune myocarditis by reprogramming inflammatory macrophages through the mTORC1-C/EBPβ-OSM pathway. Targeting OSM offers a promising therapeutic strategy for myocarditis and heart failure.
Area of Science:
- Cardiovascular Research
- Immunology
- Molecular Biology
Background:
- Myocarditis, an inflammation of the heart muscle, can lead to heart failure.
- Macrophage activation and metabolic changes drive heart inflammation and injury.
- Current therapies for myocarditis are limited.
Purpose of the Study:
- To investigate the therapeutic effects of rapamycin on autoimmune myocarditis.
- To elucidate the mechanisms by which rapamycin reprograms macrophages in myocarditis.
- To explore the role of macrophage-cardiomyocyte communication in myocarditis pathogenesis.
Main Methods:
- Experimental autoimmune myocarditis (EAM) induced in mice.
- Rapamycin treatment during the inflammatory phase.
- Cardiac function assessment via echocardiography and Millar catheterization.
- Single-cell RNA sequencing (scRNA-seq) to analyze cardiac immune cells.
- Functional validation using Seahorse assays and in vivo OSM neutralization.
Main Results:
- Rapamycin improved cardiac function and reduced inflammation and fibrosis in EAM mice.
- scRNA-seq showed rapamycin inhibited mTOR signaling, restored mitochondrial metabolism, and suppressed inflammatory pathways in macrophages.
- Rapamycin specifically targeted pathogenic Cxcl9+ macrophages by disrupting the mTORC1-C/EBPβ axis.
- Therapeutic OSM neutralization mimicked rapamycin's protective effects.
Conclusions:
- Rapamycin preserves cardiac function in autoimmune myocarditis by reprogramming macrophages via the mTORC1-C/EBPβ-OSM axis.
- Targeting OSM is a validated therapeutic strategy for myocarditis.
- This study highlights a translational approach for treating myocarditis and chronic inflammatory cardiomyopathy.
Background:
Myocarditis is an inflammatory disease of the myocardium that can progress to chronic inflammatory cardiomyopathy and heart failure. Aberrant activation and metabolic reprogramming of macrophages drive myocardial inflammation and injury, yet effective targeted therapies remain limited.
Methods:
Experimental autoimmune myocarditis (EAM) was induced in BALB/c mice by α-myosin heavy chain immunization. Rapamycin was administered during the inflammatory phase. Cardiac function and injury were evaluated by echocardiography, Millar catheterization, histology, qPCR, and ELISA. Single-cell RNA sequencing (scRNA-seq) of cardiac CD45+ cells, coupled with pseudotime trajectory, SCENIC regulon, and NicheNet analyses, was performed to delineate macrophage heterogeneity, lineage dynamics, and macrophage-cardiomyocyte communication. Functional validation included Seahorse metabolic assays and Cebpb-overexpressing bone marrow-derived macrophage (BMDM)-cardiomyocyte co-culture experiments, along with in vivo OSM-neutralizing antibody (OSM-nAb) intervention.
Results:
Rapamycin preserved cardiac function and alleviated myocardial inflammation and fibrosis in EAM mice, accompanied by reduced cytokine release and cardiac injury markers. scRNA-seq revealed that rapamycin reprogrammed cardiac monocyte-macrophages by inhibiting mTOR signaling, restoring mitochondrial metabolism, and suppressing inflammatory, glycolytic, and senescence pathways. It specifically targeted pathogenic Cxcl9+ macrophages by disrupting the mTORC1-C/EBPβ axis and limiting their differentiation from Plac8+ monocytes. Rapamycin further protected cardiomyocytes by blocking C/EBPβ-dependent OSM-mediated macrophage-cardiomyocyte crosstalk. Therapeutic OSM neutralization in vivo similarly mitigated myocardial inflammation and fibrosis while preserving ventricular contractility.
Conclusion:
Rapamycin preserves cardiac function in autoimmune myocarditis by reprogramming Cxcl9+ macrophages via the mTORC1-C/EBPβ-OSM axis. Targeting OSM provides mechanistic validation and highlights a translational therapeutic strategy for myocarditis and chronic inflammatory cardiomyopathy.
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