S100A9 Aggravates Cardiac Fibrosis by TLR4/PGC-1α Mediated Macrophage-Myofibroblast Crosstalk.

Fibrosis is a critical component of ventricular remodelling after myocardial ischemia, and the activation and expansion of cardiac fibroblasts represent key drivers of this process. Our previous work identified S100A9-dependent macrophage-to-myofibroblast transition (MMT) as a newly recognized source of myofibroblasts in the post-MIR heart. However, the mechanisms by which S100A9 regulates MMT remain incompletely understood. Here, using multiple genetically engineered mouse models, MIR and MI model, and in vitro multicellular co-culture systems, we investigated the role of S100A9 in regulating fibroblast-derived migrasome release during MMT. We found that macrophage-derived S100A9 promotes mitochondrial dysfunction and migrasome release in cardiac fibroblasts through TLR4/PGC1α signalling following MIR. These fibroblast-derived migrasomes, in turn, activate integrin/Src signalling in macrophages, triggering MMT and accelerating cardiac fibrosis. Importantly, we delineate how macrophage-derived S100A9 orchestrates crosstalk between fibroblasts and immune cells and identify migrasome-mediated activation of MMT as a previously unrecognized mechanism driving post-MIR fibrotic remodelling. Our findings suggest that targeting S100A9-induced migrasome release and downstream MMT signalling may represent a promising therapeutic strategy to mitigate pathological cardiac fibrosis.