Cardiac repair after myocardial infarction: A two-sided role of inflammation-mediated

Abstract

Myocardial infarction is the leading cause of death and disability worldwide, and the development of new treatments can help reduce the size of myocardial infarction and prevent adverse cardiovascular events. Cardiac repair after myocardial infarction can effectively remove necrotic tissue, induce neovascularization, and ultimately replace granulation tissue. Cardiac inflammation is the primary determinant of whether beneficial cardiac repair occurs after myocardial infarction. Immune cells mediate inflammatory responses and play a dual role in injury and protection during cardiac repair. After myocardial infarction, genetic ablation or blocking of anti-inflammatory pathways is often harmful. However, enhancing endogenous anti-inflammatory pathways or blocking endogenous pro-inflammatory pathways may improve cardiac repair after myocardial infarction. A deficiency of neutrophils or monocytes does not improve overall cardiac function after myocardial infarction but worsens it and aggravates cardiac fibrosis. Several factors are critical in regulating inflammatory genes and immune cells' phenotypes, including DNA methylation, histone modifications, and non-coding RNAs. Therefore, strict control and timely suppression of the inflammatory response, finding a balance between inflammatory cells, preventing excessive tissue degradation, and avoiding infarct expansion can effectively reduce the occurrence of adverse cardiovascular events after myocardial infarction. This article reviews the involvement of neutrophils, monocytes, macrophages, and regulatory T cells in cardiac repair after myocardial infarction. After myocardial infarction, neutrophils are the first to be recruited to the damaged site to engulf necrotic cell debris and secrete chemokines that enhance monocyte recruitment. Monocytes then infiltrate the infarct site and differentiate into macrophages and they release proteases and cytokines that are harmful to surviving myocardial cells in the pre-infarct period. As time progresses, apoptotic neutrophils are cleared, the recruitment of anti-inflammatory monocyte subsets, the polarization of macrophages toward the repair phenotype, and infiltration of regulatory T cells, which secrete anti-inflammatory factors that stimulate angiogenesis and granulation tissue formation for cardiac repair. We also explored how epigenetic modifications regulate the phenotype of inflammatory genes and immune cells to promote cardiac repair after myocardial infarction. This paper also elucidates the roles of alarmin S100A8/A9, secreted frizzled-related protein 1, and podoplanin in the inflammatory response and cardiac repair after myocardial infarction.

Keywords: cardiac repair; epigenetic modifications; inflammation; inflammatory cells; myocardial infarction; two-way adjustment.

FIGURE 1

Immune cells are involved in damage and repair after myocardial infarction. After MI, DAMPs are released by necrotic cardiomyocytes and damaged extracellular matrix fragments, which activate TLRs and NF-κB signaling in cardiomyocytes, promote the release of inflammatory factors and chemokines, and leukocyte infiltration into damaged tissues. The inflammatory response is triggered by the disruption of antioxidant mechanisms, massive release of ROS, and significant activation of the complement system. Neutrophils are recruited into the infarct site within the first few minutes after MI, interact with endothelial cells via integrins and ICAM-1, perform phagocytosis of necrotic cell debris, and initiate an apoptotic program with corresponding changes on the cell surface to promote cytokine clearance and eventual clearance by macrophages. Circulating lipoxin A4, resolvin E1, and AnxA1 induce neutrophil apoptosis and stimulate macrophage polarization toward an anti-inflammatory phenotype. Apoptotic neutrophils release alpha-defensins, a cascade of proteins that increases macrophage phagocytic activity and inhibits their ability to release inflammatory factors. Therefore, clearance of apoptotic neutrophils is considered the beginning of cardiac repair after MI. In the following hours, B and T lymphocytes are also recruited to the damaged site, promoting the recruitment of circulating monocytes to the area of infarction. Monocytes in the spleen, regulated by ANG II, also migrated to the location of myocardial injury, driving CCR2-dependent monocyte migration via MCP-1 binding to CCR2 and promoting the expression of CCL2 and CCL7. Pro-inflammatory Ly6C^high monocytes differentiate into proinflammatory macrophages (M1), which release inflammatory factors such as IL-1, TNF-α, and IL-12, exert phagocytosis and secrete protein hydrolases to promote digestion of tissue and clearance of necrotic debris in the infarcted region. Over time, reparative Ly6C^low monocytes become the predominant subtype and differentiate into anti-inflammatory macrophages (M2) that express pro-repair mediators such as IL-10, VEGF, and TGF-β1 to suppress the inflammatory response, promote myofibroblast proliferation, angiogenesis, and collagen fiber deposition, and promote cardiac repair after MI. In addition, regulatory T cells regulate macrophage phenotype through secretion of IL-10, VEGF, TGF-β1, or contact-dependent pathways to facilitate the regression of cardiac inflammation and improve cardiac function after MI.