2 Macrophages
Macrophages are an essential component of mammals, distributed throughout the body to maintain immunological homeostasis in tissues(Russell et al., 2019). They display extraordinary plasticity and the ability to alter their functional phenotype in response to the local environment(Koelwyn et al., 2018). Macrophages must rely on metabolic pathways and metabolic intermediates to govern cell fate to conduct various actions essential for host defense and tissue repair, such as phagocytosis of apoptotic cells and infections (intrinsic cellular processes and exogenous cellular responses)(Groh et al., 2018). Macrophages are a significant component of plaque in atherosclerosis. Retention of cholesterol-rich lipoproteins within the walls of large and medium-sized arteries results in sterile inflammation and promote the accumulation of cholesterol-rich macrophage foam cells that is contribute to plaque development(Robbins et al., 2013; Andrejeva and Rathmell, 2017; van Tuijl et al., 2019). These macrophage foam cells have limited migratory capacity and produce pro-inflammatory cytokines and chemokines that recruit immune response enhancers, such as extra monocytes, T cells, and neutrophils(Lachmandas et al., 2016; Tabas and Lichtman, 2017; Groh et al., 2018). The complex milieu of plaques induces various activation modes of macrophages with a more complex and varied reconfiguration of metabolic pathways than typically activated macrophage phenotypes(O’Neill et al., 2016).
A significant contributor to the development of atherosclerosis is cellular oxidative stress(Moore et al., 2013; Sergin et al., 2014). Mitochondrial oxidative metabolism, NADPH oxidase, peroxidase, NO synthase, cyclooxygenase, and lipoxygenase generate reactive oxygen species (ROS) in macrophages during atherosclerosis(West et al., 2015; Mills et al., 2017). However, oxidative stress alters the transcription and regulation of antioxidant genes in plaque macrophages(Marsch et al., 2014; Jha et al., 2015). The inhibition of mitochondrial transport of the antioxidant glutathione (GSH) exacerbates arterial wall inflammation(Tabas and Glass, 2013). For instance, NADPH oxidase-derived ROS from macrophages has been demonstrated to increase LDL oxidation in artery walls, enhancing the development of macrophage foam cells.
Moreover, mtROS formed as byproducts of the electron transport chain process can damage mitochondrial DNA (mtDNA), proteins, and lipids(Van den Bossche et al., 2017). These have been demonstrated to increase atherosclerosis in mice. Oxidation or release of mitochondrial DNA can activate innate immune signaling pathways in macrophages, including the CpG DNA receptor TLR9, the NLRP3 inflammasome, and the cyclic GMP-AMP synthase (cGAS) - Stimulator of interferon genes (STING) pathway(Guo et al., 2015; Cochain et al., 2018). Relevant studies have also confirmed that reducing mitochondrial oxidative stress in macrophages decreases atherosclerotic load in mice and avoids inflammation in plaques(Van den Bossche et al., 2016; Correction to: Mitochondrial respiration is reduced in atherosclerosis, promoting necrotic core formation and reducing relative fibrous cap thickness, 2018). Oxidative stress greatly influences the metabolic reprogramming of macrophages, leading to a greater dependence on glycolysis(Folco and Sukhova, 2014; Nomura et al., 2016). The key to this metabolic transition is activating the hypoxia-inducible factor 1 (HIF-1) transcription factor, which stimulates the expression of GLUT-1 and glycolytic enzymes (such as HK, PFK, and PFKB3), enhances glucose absorption, and restricts oxidative phosphate acidification and lactic acid generation(Baardman et al., 2015; Tan et al., 2015; Shirai et al., 2016). Activation of the HIF-1 pathway, particularly in macrophages, regulates oxidative stress-induced metabolic alterations and inflammatory consequences in atherosclerotic lesions(Mills et al., 2018). In atherosclerotic plaques, oxidative stress-induced HIF-1 expression leads to pathologically elevated GLUT1, GLUT3, HK1, and HK2 in macrophages, whereas macrophages lacking HIF-1 produce inflammatory genes (e.g., monocytogenes)(Stienstra et al., 2017; Miska et al., 2022). This pathogenic response is characterized by decreased expression of nuclear chemoattractant protein-1 (osteopontin) and apoptosis, suggesting that HIF-1 activation and enhanced glycolysis are essential(Littlewood-Evans et al., 2016).