Cells of the Immune System in Cardiac Remodeling: Main Players in Resolution of Inflammation and Repair After Myocardial Infarction

Abstract

The burden of heart failure (HF), developing after myocardial infarction MI, still represents a major issue in clinical practice. Failure of appropriate resolution of inflammation during post-myocardial injury is associated with unsuccessful left ventricular remodeling and underlies HF pathogenesis. Cells of the immune system have been shown to mediate both protective and damaging effects in heart remodeling. This ambiguity of the role of the immune system and inconsistent results of the recent clinical trials question the benefits of anti-inflammatory therapies during acute MI. The present review will summarize knowledge of the roles that different cells of the immune system play in the process of post-infarct cardiac healing. Data on the phenotype, active molecules and functions of the immune cells, based on the results of both experimental and clinical studies, will be provided. For some cellular subsets, such as macrophages, neutrophils, dendritic cells and lymphocytes, an anti-inflammatory activity has been attributed to the specific subpopulations. Activity of other cells, such as eosinophils, mast cells, natural killer (NK) cells and NKT cells has been shown to be highly dependent of the signals created by micro-environment. Also, new approaches for classification of cellular phenotypes based on the single-cell RNA sequencing allow better understanding of the phenotype of the cells involved in resolution of inflammation. Possible perspectives of immune-mediated therapy for AMI patients are discussed in the conclusion. We also outline unresolved questions that need to be solved in order to implement the current knowledge on the role of the immune cells in post-MI tissue repair into practice.

Keywords: cellular heterogeneity; immune cells; immune metabolism; inflammation; myocardial infarction; myocardial remodeling; resolution.

Figure 1

Summary characteristics of immune cells involved in development and resolution of inflammation post-myocardial infarction. Cells of the immune system may input either successful or unsuccessful myocardial remodeling after myocardial infarction, being involved in all the three phases of cardiac repair: inflammatory phase; reparative and proliferative phase; maturation phase. Some cellular populations (monocytes, macrophages, lymphocytes) are represented by two or more subsets with opposite or complementary effects. At the same time, some immune cells may exhibit either inflammatory or reparative properties, depending on the nature of the signal and cellular milieu (eosinophils, dendritic cells, mast cells, NK cells, iNKT cells). Possibility exists that new distinct subpopulations of immune cells are yet to be described, and inflammatory and reparative functions will further be ascribed to different cellular subsets. CCL CC, Chemokine ligand; CD, Cluster of differentiation; ECP, Eosinophil cationic protein; FGF, Fibroblast growth factor; IFN, Interferon; Ig, Immunoglobulin; IL, Interleukin; IL-1Ra, Interleukin-1 receptor antagonist; MBP, Major basic protein; MMP, Matrix metalloproteinase; MPO, Myeloperoxidase; NO, Nitric oxide; ROS, Reactive oxygen species; TGF, Transforming growth factor; TNF, Tumor necrosis factor; VEGF, Vascular endothelial growth factor; Question marks indicate absent or incomplete data and facts that have not been sufficiently studied for myocardial infarction.

Figure 2

Pathways of metabolic reprogramming in immune cells. Activation of mTOR during hypoxia and stimulation of PRR by DAMPs or antigen receptors on T- and B-lymphocytes by antigens leads to the sustained stimulation of HIF-1α, which in turn activates glycolysis and pentose-phosphate pathway, breaking down tricarboxylic acid (TCA) cycle. All of the above mentioned metabolic pathways are associated with high rate of ATP production, generation of biosynthetic precursors (nucleotides, fatty acids, ribose, amino acids), diversion of immune suppressive factors such as phosphoenolpyruvate into glycolytic pathway and production of cofactors (such as NADH). As a consequence cells of the immune system are activated and acquire inflammatory phenotype. Restoration of the normal oxygen supply or anti-inflammatory signaling, sometimes combined with checkpoint (PD-1) activation, stimulates AMPK, characterized by the suppressive activity towards mTOR. AMPK supports integrity of TCA, stimulates OXPHOS and fatty acid oxidation, minimizing ATP consumption and inhibiting cell cycle and biosynthesis. Switching from catabolism to anabolism represents a stimulus for the development of anti-inflammatory and memory cells. AMPK, AMP activated protein kinase; ATP, Adenosine triphosphate; CD, Cluster of differentiation; DC, Dendritic cell; HIF, Hypoxia induced factor; IL, Interleukin; MDSC, Myeloid derived suppressor cell; mTOR, Mammalian target of rapamycin; OXPHOS, Oxidative phosphorylation; PPP, Pentose phosphate pathway; PRR, Pattern recognition receptors; TCA, Tricarboxylic acid cycle; Treg, T regulatory lymphocytes.