Abstract 55: Opposing Roles Of Distinct Macrophage Lineages In Heart Failure And Cardiac Recovery

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Why inflammation is simultaneously deleterious following injury and essential for tissue repair continues to be fundamentally important and debated question. Recently, a new paradigm has emerged in the macrophage field: that organs are replete with resident macrophages of embryonic origin, distinct from monocyte-derived macrophages. This added complexity raises the question of whether distinct immune cells drive inflammatory and reparative activities following injury. Previous work has demonstrated that the neonatal heart has a remarkable capacity for tissue repair compared to the adult, offering an ideal context to examine these concepts. We hypothesized that unrecognized differences in macrophage composition in the neonatal and adult heart represents a key determinant of cardiac recovery. To test this hypothesis, we generated a novel cardiomyocyte ablation model and demonstrated that following injury neonatal mice expand a population of resident cardiac macrophages derived from embryonic lineages, which generate minimal inflammation and are necessary and sufficient for cardiac recovery through promotion of cardiomyocyte proliferation and angiogenesis. During homeostasis the adult heart also contained embryonic-derived macrophages with similar properties. However, following injury these cells disappeared, and instead, the adult heart recruited pro-inflammatory monocytes and monocyte-derived macrophages that lacked reparative activities. Inhibition of monocyte recruitment into the injured adult heart preserved embryonic-derived macrophage subsets, reduced inflammatory cytokine and chemokine production, and enhanced tissue repair. Together, these findings indicate that embryonic-derived macrophages, rather than monocyte-derived macrophages, are key mediators of cardiac recovery. Therapeutics targeting distinct macrophage and monocyte lineages may serve as novel treatments for heart failure.

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