Macrophage Polarization in Myocardial Ischemia‒Reperfusion Injury: Pathophysiology and Therapeutic Targets

Abstract

Myocardial infarction is a significant contributor to both morbidity and mortality worldwide. An effective therapeutic strategy for myocardial infarction is myocardial reperfusion via percutaneous coronary intervention and thrombolytic therapy. However, reperfusion may cause another inflammatory injury to surviving cardiomyocytes, inducing further cardiomyocyte death, increasing infarct size and even leading to heart failure. Current clinical interventions mostly target a single pathology and fail to effectively regulate the repair process in the later stages of injury, resulting in limited therapeutic efficacy. Recent studies have shown that macrophages play a dual role in ischemia‒reperfusion injury: dynamic changes in their phenotype directly determine the balance between the inflammatory response and tissue repair. In addition, macrophages play a key intersection role in multiple pathological mechanisms, including but not limited to, the regulation of oxidative stress, the drive of programmed cell death, and the remodeling of the microenvironment. This review summarizes the mechanisms of macrophage injury in myocardial ischemia‒reperfusion and potential strategies for macrophage-centric targeted therapy. Currently, most studies on potential therapeutic targets are still at the animal experimental stage. Owing to simplified disease models, macrophage therapy is still not well studied in terms of target mechanisms and microenvironmental metabolic reprogramming. In addition, the clinical feasibility of targeted therapies remains to be verified owing to their low delivery efficiency and off-target effects, and further clinical studies are needed to confirm the safety and efficacy of these therapies. In the future, macrophage-related drug research is expected to lead to breakthroughs in the treatment of reperfusion injury.

Keywords: inflammatory response; macrophage polarization; myocardial ischemia‒reperfusion injury; treatment.

Figure 1

Macrophages and myocardial ischemia‒reperfusion injury. In the early reperfusion stage, DAMPs released by damaged cardiomyocytes promote the polarization of circulating monocytes into proinflammatory M1 macrophages. On the one hand, M1 macrophages recruit immune cells and promote the formation of a local inflammatory microenvironment by producing many proinflammatory factors. On the other hand, M1 macrophages produce many types of ROS, which induce oxidative stress, pyroptosis, autophagy, and ferroptosis, aggravating myocardial injury. In the late reperfusion stage, M1 macrophages are replaced by anti-inflammatory M2 macrophages, which promote the regression of inflammation and fibrous repair after injury through a series of anti-inflammatory cytokines and the production of angiogenic cytokines to promote vascular regeneration. In addition, M2 macrophages phagocytose dead cells and debris through efferocytosis, promoting the resolution of the inflammatory response and lymphatic vessel regeneration. M2 polarization of macrophages is an essential mechanism of injury reduction, revascularization, and myocardial remodeling after reperfusion. By Figdraw.