MMP12 induces fibrogenic macrophage differentiation to drive granuloma-associated cardiac fibrosis.

Summary

Using a myeloid-specific Tsc2 deletion model, single-cell sequencing, human and murine macrophage experiments, and in vivo inhibition, the study identified MMP12 as a macrophage-intrinsic driver of fibrogenic macrophage differentiation. MMP12 inhibition disrupted granuloma architecture, reduced fibroblast activation and myocardial fibrosis, and improved cardiac conduction, supporting a therapeutic axis distinct from upstream mTORC1 inhibition.

Key Findings

• mTORC1 activation generated a fibrogenic macrophage population through a TGF-beta-dependent monocyte-to-macrophage differentiation process.
• MMP12 was identified as a macrophage-intrinsic inducer and dominant effector of the fibrogenic program.
• Selective MMP12 inhibition reduced granuloma architecture, fibroblast activation, myocardial fibrosis, and conduction abnormalities in vivo.

Clinical Implications

MMP12-related pathways could support biomarker development and targeted antifibrotic therapy in cardiac sarcoidosis, particularly for patients at risk of progressive conduction disease. The findings are preclinical and should not yet replace immunosuppressive or device-based management.

Limitations

• The principal disease model was experimental and may not reproduce the full heterogeneity of human cardiac sarcoidosis.
• The therapeutic effects of MMP12 inhibition were demonstrated preclinically, without human treatment or clinical safety data.
• The optimal timing, dosing, and specificity of MMP12 inhibition relative to immunosuppression remain unresolved.

Future Directions

Future work should validate MMP12 as a circulating or tissue biomarker, develop selective inhibitors suitable for cardiac disease, and test whether targeting MMP12 can prevent arrhythmias and preserve ventricular function in prospective translational studies.