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S100A9 Aggravates Cardiac Fibrosis by TLR4/PGC-1α Mediated Macrophage-Myofibroblast Crosstalk
Yiting Zhao1,2, Yaqin Zhang3, Qiang Yuan2
1Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Insights
Macrophage-derived S100A9 triggers cardiac fibroblast dysfunction and migrasome release after myocardial infarction (MI). This process drives macrophage-to-myofibroblast transition (MMT), accelerating cardiac fibrosis.
Area of Science:
- Cardiovascular Biology
- Immunology
- Fibrosis Research
Background:
- Cardiac fibrosis, driven by fibroblast activation, is key to ventricular remodeling post-myocardial infarction (MI).
- Macrophage-to-myofibroblast transition (MMT) is a newly identified source of myofibroblasts following MI, dependent on S100A9.
- The precise mechanisms linking S100A9 to MMT require further elucidation.
Purpose of the Study:
- To investigate the role of S100A9 in regulating fibroblast-derived migrasome release during MMT post-MI.
- To understand the signaling pathways involved in S100A9-mediated MMT and cardiac fibrosis.
Main Methods:
- Utilized genetically engineered mouse models of myocardial infarction (MI) and in vitro multicellular co-culture systems.
- Investigated the impact of macrophage-derived S100A9 on cardiac fibroblast mitochondrial function and migrasome release.
- Analyzed the downstream signaling pathways including TLR4/PGC1α and integrin/Src signaling.
Main Results:
- Macrophage-derived S100A9 induces mitochondrial dysfunction and migrasome release in cardiac fibroblasts via TLR4/PGC1α signaling post-MI.
- Fibroblast-derived migrasomes activate integrin/Src signaling in macrophages, promoting MMT and accelerating cardiac fibrosis.
- Identified a novel mechanism of crosstalk between fibroblasts and immune cells mediated by S100A9 and migrasomes.
Conclusions:
- Macrophage-derived S100A9 orchestrates a novel pathway involving fibroblast migrasome release and MMT that drives post-MI cardiac fibrosis.
- Targeting S100A9-induced migrasome release and MMT signaling presents a potential therapeutic strategy for mitigating cardiac fibrosis.
Abstract:
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.
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