Macrophage-driven cardiac inflammation and healing: insights from homeostasis and myocardial infarction

Abstract

Early and prompt reperfusion therapy has markedly improved the survival rates among patients enduring myocardial infarction (MI). Nonetheless, the resulting adverse remodeling and the subsequent onset of heart failure remain formidable clinical management challenges and represent a primary cause of disability in MI patients worldwide. Macrophages play a crucial role in immune system regulation and wield a profound influence over the inflammatory repair process following MI, thereby dictating the degree of myocardial injury and the subsequent pathological remodeling. Despite numerous previous biological studies that established the classical polarization model for macrophages, classifying them as either M1 pro-inflammatory or M2 pro-reparative macrophages, this simplistic categorization falls short of meeting the precision medicine standards, hindering the translational advancement of clinical research. Recently, advances in single-cell sequencing technology have facilitated a more profound exploration of macrophage heterogeneity and plasticity, opening avenues for the development of targeted interventions to address macrophage-related factors in the aftermath of MI. In this review, we provide a summary of macrophage origins, tissue distribution, classification, and surface markers. Furthermore, we delve into the multifaceted roles of macrophages in maintaining cardiac homeostasis and regulating inflammation during the post-MI period.

Keywords: Hemostasis; Inflammation; Macrophage; Myocardial infarction; Polarization.

Fig. 1

Origin and development of cardiac resident macrophage. During embryonic development, cardiac-resident macrophages primarily originate from the yolk sac or fetal liver and differentiate from monocytes. Notably, monocytes derived from the yolk sac initiate the process of differentiation and migration to the heart earlier, whereas those derived from the fetal liver undergo this process at a later stage. These macrophages derived from embryonic sources colonize the heart and exhibit limited self-replenishment through in situ proliferation. In contrast, bone marrow-derived monocytes start infiltrating the heart at 14 days postpartum and differentiate into an additional major population of cardiac-resident macrophages, primarily supplemented by the continuous colonization of peripheral blood monocytes during later stages. Created with BioRender.com

Fig. 2

Advancements in the understanding of macrophage populations and functions after MI. According to the traditional view, macrophages were classified into two populations: pro-inflammatory M1 macrophages and reparative M2 macrophages. Initial investigations into cardiac macrophage populations after myocardial infarction (MI) seemed to support this established model. However, recent evidence, not only from heart but also from other tissues, has unveiled a remarkable heterogeneity and plasticity in macrophage development, phenotype, and function. The introduction of single-cell RNA sequencing has significantly advanced the understanding of distinct macrophage clusters and their phenotypes after MI. These emerging findings in macrophage biology have provided insight into the shortcomings of non-specific immunosuppressive strategies and have paved the way for novel therapeutic interventions targeting heart failure prevention following MI. Adapted from “Healthy vs. Diseased Heart (Layout)”, by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates

Fig. 3

Metabolic reprogramming of macrophages after MI. In the early phase post myocardial infarction (MI), macrophages infiltrate the injured myocardium and secrete pro-inflammatory cytokines. Under hypoxic stimuli, there is a shift in their energy metabolism, favoring glycolysis through the pentose phosphate pathway (PPP). Additionally, there is rewiring of the tricarboxylic acid cycle (TCA) and an elevation in mitochondrial reactive oxygen species (mtROS) levels. As a result, substrate oxidation and adenosine triphosphate (ATP) synthesis via oxidative phosphorylation (OXPHOS) are reduced. In contrast, macrophages adopt a phagocytotic phenotype during the wound healing phase. This transition is driven by changes in the microenvironment, efferocytosis (the clearance of apoptotic cells), and further metabolic reprogramming. Consequently, macrophages switch back to oxidative metabolism and actively participate in collagen deposition, promoting tissue repair and healing processes. The balance between hypoxia-induced factor-1ɑ (HIF-1ɑ) and HIF-2ɑ is also involved in the metabolic reprogramming and phenotype switching of macrophages. HIF-1ɑ induces the conversion of I-arginine into inducible nitric oxide synthase (iNOS) while HIF-2 induces the production of arginase-1. Adapted from “Comparison Between Oxidative Eustress and Oxidative Distress”, by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates

Fig. 4

The role of macrophages in inflammation and repair after MI. In summary, macrophages play several key roles in myocardial infarction (MI): from the initial formation of atherosclerosis to stress-induced damage during the acute inflammatory phase, secretion of pro-inflammatory factors, and finally their involvement in the phagocytosis of necrotic myocardial cells, synthesis of the extracellular matrix, angiogenesis, and myocardial regeneration during the repair phase. The pro-inflammatory and anti-inflammatory effects mediated by macrophages are intertwined throughout the development of MI, and they engage in cross-talk with myocardial cells, cardiac fibroblasts, and endothelial cells. Targeting macrophage-mediated inflammation regulation is a promising clinical strategy for the effective treatment of MI in the future. Adapted from “Mechanisms of Cancer-associated Fibroblast Activation”, by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates