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).