Journal Article

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

Nichols, Colin G., Mann, Douglas L., Epelman, Slava, Lavine, Kory J., Randolph, Gwendalyn J., Weber, Kassandra J., Uchida, Keita, Schilling, Joel D., Ornitz, David M.

2014

Overview

Significance This study addresses a fundamentally important and widely debated issue in the field of inflammation, which is why inflammation can be simultaneously deleterious after injury and yet is essential for tissue repair. Recently, an important new paradigm has emerged in the macrophage field: Organs are replete with resident macrophages of embryonic origin, distinct from monocyte-derived macrophages. In this article, we use a new model of cardiac injury and show that distinct macrophage populations derived from embryonic and adult lineages are important determinants of tissue repair and inflammation, respectively. Our data suggest that therapeutics, which inhibit monocyte-derived macrophages and/or selectively harness the function of embryonic-derived macrophages, may serve as novel treatments for heart failure. 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: adults / Angiogenesis / Animals / Bacteriophages / Biological Sciences / Cardiomyocytes / DNA repair / Embryo, Mammalian - metabolism / Heart / heart failure / Inflammation / Inflammation - metabolism / Inflammation - therapy / Leukocytes / Macrophages / Macrophages - metabolism / Messenger RNA / Mice / Monocytes / Myocardium / Myocardium - metabolism / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - transplantation / Recovery of Function / Regeneration / Renovations / therapeutics / Tissue repair / Tissues / Ventricular Remodeling