Cardiac macrophages in maintaining heart homeostasis and regulating ventricular remodeling of heart diseases

Figures

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  Figure 1. M1 and M2 macrophage polarization: Upon inflammatory (LPS, INFγ, TNFα) stimuli, macrophages are polarized into inflammatory M1 phenotype by activating NF-kB inflammatory pathway, simultaneously, the metabolic pathway of M1 macrophages swifts into glycolysis and pentose phosphate pathway. M1 macrophages release inflammatory mediators including inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), reactive nitric species (RNS), tumor necrotic factor (TNF) α, interleukin (IL)-1β, IL-6, monocyte chemokine protein (MCP)-1, leading to cytotoxicity and tissue injury. When inflammatory stimuli subsides or anti-inflammatory cytokines IL-10, IL-4 and IL-13 increase, macrophages are polarized into M2 anti-inflammatory macrophage associated with the switch of metabolic pathway into oxidative phosphorylation (OXPHOS) and fatty acid b-oxidation. M2 macrophages release arginase 1 (Arg1), VEGF, IL-10 and TGF-β1, promoting to tissue repair and wound healing.

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  Figure 2. Metabolic reprogramming of M1/M2 macrophages: M1 inflammatory macrophages activate HIF1α pathway, which upregulates two key enzymes of glycolysis: 6-phosphofructose-2-kinase B (PFKFB) and pyruvate kinase M2 (PKM2), and increases activity of lactate dehydrogenase (LDH) that promotes the conversion of pyruvate to lactic acid, thus, increasing glycolysis. ATP generation from rapid glycolysis in turn inhibits mitochondria respiratory chain to reduce ATP generation from tricarboxylic acid cycle (TCA) through reduced key enzymes of TCA cycle, such as isocitrate dehydrogenase (IDH) and succinate dehydrogenase (SDH). The decreased activity of IDH and SDH increases the accumulation of substrates isocitrate and succinate in mitochondria which leak into the cytoplasm to continuously activate NF-kB and HIF1α, thus maintaining M1 macrophage activation and glycolysis. In other way, M2 macrophages have low level of glycolysis with intact TCA cycle, they generate ATP through mitochondria OXPHOS. In addition, M2 macrophages express high level of Arg1, which inhibit iNOS-derived NO production, which promotes the entry of pyruvate into the TCA cycle and inhibits glycolysis.

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  Figure 3. Acute myocardial infarction (AMI) alters cardiac macrophage subpopulation to induce pathological cardiac remodeling. After AMI, damaged or dead cardiomyocytes release MCP-1, which attracts circulatory Ly6Chi monocytes to recruit to the infarcted area and differentiate into CCR2+Ly6Chi macrophage. In other way, danger-associated molecular proteins (DAMPs) released from injury cells bind to pattern recognition receptors (PRRs) and promote the switch of CCR2-Ly6Clow cardiac resident macrophages (CRMs) into CCR2+ CRMs, resulting in the imbalance between CCR2+ CRMs and CCR2- CRMs. CCR2+ CRMs secrete pro-inflammatory cytokines ROS generation to aggravate myocardial cell injury and death and induce pathological cardiac remodeling.