Selective expansion of cardiac macrophage subtypes distinguishes their functional roles in disease and homeostasis

Rajesh K. Kasam; Ronald J. Vagnozzi; Yasuhide Kuwabara; Anne Katrine Z. Johansen; N. Scott Blair; Vikram Prasad; Suh-Chin J. Lin; Akanksha Rajput; Michelle Nieman; Jeffery D. Molkentin

doi:10.1172/JCI200194

Selective expansion of cardiac macrophage subtypes distinguishes their functional roles in disease and homeostasis

Rajesh K. Kasam,¹ Ronald J. Vagnozzi,² Yasuhide Kuwabara,¹ Anne Katrine Z. Johansen,¹ N. Scott Blair,¹ Vikram Prasad,¹ Suh-Chin J. Lin,¹ Akanksha Rajput,¹ Michelle Nieman,¹ and Jeffery D. Molkentin¹

Published June 9, 2026 - More info

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Abstract

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.

Selective expansion of cardiac macrophage subtypes distinguishes their functional roles in disease and homeostasis

Rajesh K. Kasam,¹ Ronald J. Vagnozzi,² Yasuhide Kuwabara,¹ Anne Katrine Z. Johansen,¹ N. Scott Blair,¹ Vikram Prasad,¹ Suh-Chin J. Lin,¹ Akanksha Rajput,¹ Michelle Nieman,¹ and Jeffery D. Molkentin¹

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Selective expansion of cardiac macrophage subtypes distinguishes their functional roles in disease and homeostasis

Rajesh K. Kasam,1 Ronald J. Vagnozzi,2 Yasuhide Kuwabara,1 Anne Katrine Z. Johansen,1 N. Scott Blair,1 Vikram Prasad,1 Suh-Chin J. Lin,1 Akanksha Rajput,1 Michelle Nieman,1 and Jeffery D. Molkentin1

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Rajesh K. Kasam,¹ Ronald J. Vagnozzi,² Yasuhide Kuwabara,¹ Anne Katrine Z. Johansen,¹ N. Scott Blair,¹ Vikram Prasad,¹ Suh-Chin J. Lin,¹ Akanksha Rajput,¹ Michelle Nieman,¹ and Jeffery D. Molkentin¹