Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart

KJ Lavine, S Epelman, K Uchida… - Proceedings of the …, 2014 - National Acad Sciences
KJ Lavine, S Epelman, K Uchida, KJ Weber, CG Nichols, JD Schilling, DM Ornitz
Proceedings of the National Academy of Sciences, 2014National Acad Sciences
The mechanistic basis for why inflammation is simultaneously both deleterious and essential
for tissue repair is not fully understood. Recently, a new paradigm has emerged: 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 after injury. Previous work has demonstrated that
the neonatal heart has a remarkable capacity for tissue repair compared with the adult heart …
The mechanistic basis for why inflammation is simultaneously both deleterious and essential for tissue repair is not fully understood. Recently, a new paradigm has emerged: 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 after injury. Previous work has demonstrated that the neonatal heart has a remarkable capacity for tissue repair compared with the adult heart, offering an ideal context to examine these concepts. We hypothesized that unrecognized differences in macrophage composition is a key determinant of cardiac tissue repair. Using a genetic model of cardiomyocyte ablation, we demonstrated that neonatal mice expand a population of embryonic-derived resident cardiac macrophages, which generate minimal inflammation and promote cardiac recovery through cardiomyocyte proliferation and angiogenesis. During homeostasis, the adult heart contains embryonic-derived macrophages with similar properties. However, after injury, these cells were replaced by monocyte-derived macrophages that are proinflammatory and lacked reparative activities. Inhibition of monocyte recruitment to the adult heart preserved embryonic-derived macrophage subsets, reduced inflammation, and enhanced tissue repair. These findings indicate that embryonic-derived macrophages are key mediators of cardiac recovery and suggest that therapeutics targeting distinct macrophage lineages may serve as novel treatments for heart failure.
National Acad Sciences