Key result
Enriching CCR2+ macrophages worsens cardiac fibrosis, while CX3CR1+ expansion drives inflammation but limits adverse remodeling.
Why the study?
Previous systemic loss-of-function studies suggested unique cardiac roles for CCR2+ and CX3CR1+ macrophage subtypes, prompting investigation via cardiac-specific gain of function.
Does selective expansion of cardiac macrophage subtypes (CCR2+ or CX3CR1+) alter myocardial inflammation, fibrosis, and cardiac function during homeostasis and pressure overload?
Does selective expansion of cardiac macrophage subtypes (CCR2+ or CX3CR1+) alter myocardial inflammation, fibrosis, and cardiac function during homeostasis and pressure overload?
Cardiac-specific selective enrichment of macrophage subtypes reveals their distinct roles in regulating myocardial inflammation and fibrosis during hypertrophy and homeostasis.
Should not yet guide macrophage-targeted therapies in HF; leaves open subtype-specific roles in pressure-overload remodeling.
Cardiac macrophages are broadly studied as two subtypes, tissue resident C-X3-C motif chemokine receptor 1 positive (CX3CR1 + ) that are also C-C motif chemokine receptor 2 negative (CCR2 – ), and monocyte derived CCR2 + . Previous systemic loss of function approaches suggested unique roles for each subtype in the heart with CCR2 + being inflammatory and CX3CR1 + being pro-healing. Here we employed a cardiac-specific gain of function approach to selectively enhance either macrophage subtype. A robust increase in basal CCR2 + macrophages in the heart by targeted C-C motif chemokine ligand 2 ( Ccl2 ) expression did not induce inflammation, cause fibroblast activation, or impair cardiac function. However, increased CCR2 + macrophages reciprocally diminished self-renewing tissue resident macrophages and worsened cardiac fibrosis due to pressure overload stimulation. Conversely, augmented expression of colony-stimulating factor-1 ( Csf1 ) in the heart promoted selective expansion of resident CX3CR1 + macrophages, which exerted no pathophysiological consequences at steady-state. However, pressure overload in these mice with expanded CX3CR1 + macrophages showed a CCR2 + macrophage-dependent inflammation leading to exacerbated cardiac dysfunction, simultaneously still protecting from adverse remodeling and cardiac fibrosis. In conclusion, cardiac-specific selective enrichment of macrophage subtypes shows their intricate interplay and unique functional roles in regulating myocardial inflammation and fibrosis during hypertrophy and at homeostasis.
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Kasam et al. (2026) studied Cardiac homeostasis and hypertrophy/fibrosis. Cardiac-specific expansion of CCR2+ or CX3CR1+ macrophages (via AAV9-Ccl2 or MyoAAV-Csf1) vs. AAV9-Empty or MyoAAV-Empty was evaluated on Cardiac fibrosis, inflammation, and function. Cardiac-specific selective enrichment of CCR2+ macrophages worsened cardiac fibrosis after pressure overload, whereas expansion of resident CX3CR1+ macrophages exacerbated inflammation and cardiac dysfunction but protected against adverse remodeling and fibrosis.
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