Immune cells as targets for cardioprotection: new players and novel therapeutic opportunities

Abstract

New therapies are required to reduce myocardial infarct (MI) size and prevent the onset of heart failure in patients presenting with acute myocardial infarction (AMI), one of the leading causes of death and disability globally. In this regard, the immune cell response to AMI, which comprises an initial pro-inflammatory reaction followed by an anti-inflammatory phase, contributes to final MI size and post-AMI remodelling [changes in left ventricular (LV) size and function]. The transition between these two phases is critical in this regard, with a persistent and severe pro-inflammatory reaction leading to adverse LV remodelling and increased propensity for developing heart failure. In this review article, we provide an overview of the immune cells involved in orchestrating the complex and dynamic inflammatory response to AMI-these include neutrophils, monocytes/macrophages, and emerging players such as dendritic cells, lymphocytes, pericardial lymphoid cells, endothelial cells, and cardiac fibroblasts. We discuss potential reasons for past failures of anti-inflammatory cardioprotective therapies, and highlight new treatment targets for modulating the immune cell response to AMI, as a potential therapeutic strategy to improve clinical outcomes in AMI patients. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.

Keywords: Acute myocardial infarction; Dendritic cells; Fibroblasts; Inflammation; Lymphocytes; Macrophages; Monocytes; Myocardial ischaemia/reperfusion injury.

Graphical Abstract

Figure 1

Immune cell changes several minutes to hours following AMI. Following AMI, neutrophils are recruited into the ischaemic heart. Their rapid degradation and degranulation result in an acute pro-inflammatory response and trigger monocyte infiltration in the first few hours. Novel approaches to regulate the neutrophils are RIC or IPost which modulate the expression of kinin B1 and B2 receptors in neutrophils. MIF is released by cardiomyocytes in response to ROS and hypoxia. MIF exerts compartmentalized and opposing effects after myocardial IRI mediated by CXCR2. At early reperfusion, fibroblast-derived GM-CSF release plays an important role in chemotactic attraction of neutrophils and monocytes into the infarcted myocardium. Mast cell activation and/or degranulation leads to the release of pro-inflammatory mediators while mast cell-derived renin induces reperfusion arrhythmias through the activation of RAS. IPC activates Gi-coupled receptors and stabilizes mast cells. The activation of Na⁺/H⁺ exchange attenuates MPO release and prevents post-IRI arrhythmias. Anti-RAS cardioprotection is also induced by the activation of PKC-ε and mitochondrial ALDH2.

Figure 2

Immune cell changes hours to days following AMI. Β and T lymphocytes are recruited early in the injured myocardium. B lymphocytes produce CCL7 which mediates the recruitment of Ly6C^high monocytes. The spleen provides a steady source of monocytes and they migrate to the site of myocardial injury under the regulation of IL-1β, ANG II and the binding of the chemokine ligand 2 (CCL2) to the chemokine receptor 2 (CCR2). MCP-1 and CCL7 also mediate CCR2-dependent monocyte migration. Moreover, β2-adrenergic receptors play a crucial role in the migration of monocytes/macrophages to the site of infarction following AMI. The first populations of monocytes that migrate to the site of infarction are the pro-inflammatory Ly6C^high monocytes which differentiate into activated pro-inflammatory macrophages (M1) that express IL-1β and TNF-α. Gradually, the Ly-6C^low monocytes become the predominant subtype and promote the healing response to AMI and the nuclear receptor subfamily 4, group a, member 1 (Nr4a1) is essential for Ly-6C^low monocyte production. IL-13, the CXCL12/CXCR4 axis, GABA-A receptor activity and VGSCs represent targets for the monocyte/macrophage phenotypic switch from pro-inflammatory to anti-inflammatory. The PPAR-γ-dependent anti-inflammatory mechanisms and monocyte-induced myeloid-epithelial-reproductive tyrosine kinase (MerTK) cleavage are considered as novel contributors and therapeutic targets for preventing IRI.

Figure 3

Immune cell changes in the healing period following AMI. Regulatory T cells (T_reg) undergo DC regulation and down-regulate the innate immune response. The activation of T_reg through CD28 is favourably associated with improved healing and survival. T_reg cells also determine the phenotype of cardiac fibroblasts, which affects the wound healing process. DCs might mediate the activation of CD4⁺ T cells in the infarcted area, improving cardiac function post-AMI. There is increasing evidence that miRNAs (miRs) regulate the immune system by altering the function of DCs. DCs also produce miRs and exosomes regulating the inflammatory response after AMI. Pericardial lymphoid clusters can modulate the post-AMI outcome, indicating that activation of these clusters might affect as well cardiac healing. Cardiac fibroblasts are subjected to regulation by neurohumoral signals (ANG II and aldosterone), growth factors, such as TGF-β1 and secreted mediators that bind to fibroblast cell surface receptors (cytokine and growth factor receptors, integrins, syndecans, and CD44). These signals trigger the activation of fibrogenic programmes while TGF-β1 plays a critical role in conversion of cardiac fibroblasts into an organized scar with well-aligned myofibroblasts. However, TGF-β1 stimulation profoundly alters the electrophysiological phenotype of cardiac myofibroblasts, enhancing gap junctional coupling between myofibroblasts and cardiomyocytes by increasing connexin 43, thus contributing to arrhythmogenesis in the fibrotic heart.