Functional roles of cardiac macrophage subtypes in disease and homeostasis

Cardiac macrophages are broadly studied as tissue resident C-X3-C motif chemokine Receptor 1 positive (CX3CR1+) and monocyte derived C-C motif chemokine Receptor 2 positive (CCR2+) subtypes, and previous systemic loss of function approaches suggested their differential functions in the heart. Here we employed a novel gain of function approach specific to the heart to selectively enhance either CX3CR1+ or CCR2+ macrophages. A robust increase in basal CCR2+ macrophages in the heart by targeted CCL2 expression did not induce inflammation, cause fibroblast activation, or impair cardiac function. However, sustained recruitment of CCR2+ macrophages reciprocally diminished numbers of self-renewing tissue resident macrophages at steady state, worsening cardiac fibrosis due to pressure overload induced by transverse aortic constriction. Conversely, augmented expression of colony-stimulating factor-1 in the heart promoted selective expansion of CX3CR1+ macrophages, which exerted no pathophysiological consequences at steady-state. However, transverse aortic constriction stimulation in these mice with expanded CX3CR1+ macrophages showed a CCR2+ macrophage-dependent inflammation leading to exacerbated cardiac dysfunction that were ironically still protected 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.