The Evolving Roles of Cardiac Macrophages in Homeostasis, Regeneration, and Repair

Abstract

Macrophages were first described as phagocytic immune cells responsible for maintaining tissue homeostasis by the removal of pathogens that disturb normal function. Historically, macrophages have been viewed as terminally differentiated monocyte-derived cells that originated through hematopoiesis and infiltrated multiple tissues in the presence of inflammation or during turnover in normal homeostasis. However, improved cell detection and fate-mapping strategies have elucidated the various lineages of tissue-resident macrophages, which can derive from embryonic origins independent of hematopoiesis and monocyte infiltration. The role of resident macrophages in organs such as the skin, liver, and the lungs have been well characterized, revealing functions well beyond a pure phagocytic and immunological role. In the heart, recent research has begun to decipher the functional roles of various tissue-resident macrophage populations through fate mapping and genetic depletion studies. Several of these studies have elucidated the novel and unexpected roles of cardiac-resident macrophages in homeostasis, including maintaining mitochondrial function, facilitating cardiac conduction, coronary development, and lymphangiogenesis, among others. Additionally, following cardiac injury, cardiac-resident macrophages adopt diverse functions such as the clearance of necrotic and apoptotic cells and debris, a reduction in the inflammatory monocyte infiltration, promotion of angiogenesis, amelioration of inflammation, and hypertrophy in the remaining myocardium, overall limiting damage extension. The present review discusses the origin, development, characterization, and function of cardiac macrophages in homeostasis, cardiac regeneration, and after cardiac injury or stress.

Inflammatory Burden and Immunomodulative Therapeutics of Cardiovascular Diseases

“…Phagocytosis by polymorphonuclear leukocytes was found to be induced post MI. These findings further confirmed the role of cardiac macrophages in homeostasis, regeneration, and repair after ischaemic events [ 18 ]. The second postulation was established to modulate MMP and its proteolytic products to regulate cardiac remodelling.…”

Fibrin, Bone Marrow Cells and Macrophages Interactively Modulate Cardiomyoblast Fate

“…However, the crosstalk between cardiac cells and macrophages is essential for cardiac homeostasis [7,11,47,[53][54][55]. In addition to their multifaceted roles in ECM modulation, cardiac electrical conduction and mitochondrial homeostasis [56][57][58], we reinforce the importance of anti-inflammatory macrophages in regulating proliferative cell fate. The present in vitro results suggest that macrophage plasticity and anti-inflammatory environment are both necessary for modifying cardiomyoblast cell size and proliferation.…”

Early Protective Role of Inflammation in Cardiac Remodeling and Heart Failure: Focus on TNFα and Resident Macrophages

“…In particular, cardiac remodeling is a complex inflammatory syndrome where Mφ play a determinant role. Mφ reside in the tissue in the absence of injury and inflammation, but also play a major role following myocardial stress, where they can be protective or harmful [ 136 , 137 ]. Mφ influence tissue homeostasis, repair and regeneration in response to injury and modulating cardiac hypertrophy and HF [ 138 , 139 , 140 ].…”

“…Strikingly, recent mapping and genetic depletion studies allowed to begin to decipher the functional roles of various Mφ populations and identify functions far beyond a phagocytic and immunologic role, e.g., maintaining mitochondrial function, facilitating cardiac conduction, and promoting coronary development and lymphangiogenesis [ 136 , 163 ].…”