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

Abstract

Cardiac sarcoidosis (CS) is a granulomatous inflammatory disease that frequently progresses to irreversible myocardial fibrosis and lethal conduction abnormalities. While mTORC1-dependent macrophage activation has been implicated in this process, exactly how granulomatous inflammation is mechanistically converted into fibrotic remodeling at the level of macrophage effector function remains unknown. We employed a mouse model with myeloid-specific Tsc2 deletion that recapitulates key features of human cardiac sarcoidosis. Single-cell RNA sequencing, histopathology, bioinformatic analyses, in vitro functional studies in murine and human macrophages, and in vivo pharmacologic inhibition were integrated to define macrophage-intrinsic mechanisms driving granuloma-associated cardiac fibrosis. Constitutive mTORC1 activation induced a fibrogenic macrophage (FibMac) population in the heart characterized by expression of Cd63, Spp1, Gpnmb, and Fabp5 and arising through a TGF-β-dependent monocyte-to-FibMac differentiation process. We identified matrix metalloproteinase 12 (MMP12) as macrophage-intrinsic inducer and dominant effector of this program. Recombinant MMP12 was sufficient to enforce fibrogenic macrophage differentiation, promote macrophage clustering and epithelioid features in both mouse and human macrophages. Conversely, selective MMP12 inhibition disrupted granuloma architecture, reduced fibroblast activation, and attenuated myocardial fibrosis in vivo, with concomitant improvement of cardiac conduction. In human CS tissue, MMP12 colocalized with FibMac markers within granulomas, and reanalysis of published human fibrosis datasets revealed MMP12 expression within analogous fibrogenic macrophage populations. Our findings uncover MMP12 as a macrophage-intrinsic inducer and sustainer that links fibrogenic macrophage identity to granuloma architecture and cardiac fibrosis in sarcoidosis. Targeting this effector axis provides a therapeutic strategy distinct from upstream mTORC1 inhibition.