It is generally accepted that high-risk factors, such as hyperlipidemia, smoking, hypertension, obesity, history of heart disease, and diabetes (21), alter the role of the vascular endothelial cells (ECs) semipermeable barrier and affect its ability to regulate the exchange of fluids, nutrients, and metabolites (22). This results in damage to the vascular endothelium, which in turn advances AS. Among them, the formation of thrombosis is caused by certain inflammation, and it will further promote inflammation (23).

Impaired EC function is activated to allow low-density lipoprotein cholesterol (LDL-C) to enter the endangium, where it is modified to oxidized LDL-C (OX-LDL) by free radicals secreted by recruited monocytes. OX-LDL activates the expression of chemokines and adhesion factors (monocyte chemoattractant protein interleukin (MCP)-1, interleukin (IL)-8, vascular cell adhesion molecule (VCAM)-1, endothelial cell (E/P) selection) in ECs and recruits circulating monocytes. OX-LDL recruits more immune cells (T cells, B cells, mast cells, and other immune cells) to the lesion, which together promote plaque formation (24, 25). Recruited monocytes in a local microenvironment enriched with growth factors and pro-inflammatory cytokines subsequently differentiate predominantly into M1 macrophages (26). Macrophages, especially M1 macrophages and SMC-derived macrophages, rapidly recognize and phagocytose OX-LDL via scavenger receptors on their surface, transforming it into foam cells that cause the earliest AS lesions (27, 28). As the disease progresses, accumulation of foam cells, localized necrosis, and fibrous cap formation lead to the formation of stable or unstable plaques. In the late stage of atherosclerosis, plaque instability eventually leads to plaque rupture, hemorrhage, and thrombosis due to hemodynamic changes, stress and inflammatory responses (21).

Atherosclerotic plaques are composed of extracellular lipid particles, foam cells, and debris that accumulate within the intima of the arterial wall to form a lipid or necrotic core. The core is encapsulated by a layer rich in collagen fibers, elastin fibers, SMCs, and extracellular matrix called the fibrous cap (29). The ratio of M1 to M2 varies at different stages and locations of AS. Plaques tend to stabilize when M2 macrophages predominate; plaques stability decrease when M1 macrophages infiltrate. Especially the presence of M1 macrophages in the most unstable plaque shoulder will increase necrotic core formation and plaque fragility. In general, there were far more M1 macrophages than M2 in the core; in the region of the fiber cap, the ratio of the two subtypes was similar (30), which is presented in Figure 2 .

Typically activated macrophages, M1 macrophages, are a phenotype characterized by pro-inflammation (31). M1 macrophages focus on the release of inflammatory mediators, killing and clearance of pathogenic microorganisms, and tumor-killing activity. During AS development, macrophages are stimulated by cholesterol crystals, interferon-γ (IFN-γ), lipopolysaccharide (LPS), ox-LDL, Toll-like receptor (TLR) ligands, and the remaining proinflammatory cytokines and are activated to exhibit predominantly pro-inflammatory M1 macrophages (32). Therefore, M1 macrophages secrete pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), IL-1β, IL-6, and IL-12, as well as nitric oxide (NO) and reactive oxygen species (ROS) (33). Among them, IFN-γ is the main cytokine associated with M1 activation and a major product of T helper (Th)1 cells (34). LPS promotes the expression and secretion of pro-inflammatory cytokines (e.g., IFN-β, IL-12, TNF, IL-6, and IL-1β), chemokines (e.g., CCL2, CXC chemokine ligand (CXCL) 10, and CXCL11), and antigen-presenting molecules (e.g., major histocompatibility complex (MHC) members, costimulatory molecules, and antigen-processing peptidases) (35). In addition, granulocyte macrophage colony-stimulating factor (GM-CSF) is the newest member of the M1 class of stimulators. GM-CSF is produced by a variety of cells, including macrophages and thin-walled cells, and induces the secretion of the cytokines of IL-6, IL-8, G-CSF, M-CSF, TNF, and IL-1β by monocytes and macrophages, but to a lesser extent than LPS (5).

Functionally, M1 macrophages participate in pathogen clearance and induce tissue damage by activating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which generates ROS. Simultaneously, M1 macrophages express chemokine receptor ligands, such as CXCL-9, CXCL-10, and CXCL-5, to promote recruitment of Th1 cells and natural killer cells to generate a sustained inflammatory response that is critical for elimination of cellular pathogens. In the microecological environment of AS, pro-inflammatory M1 macrophages cause persistent inflammation with enhanced phagocytosis and migration, thus sustaining damage to surrounding tissues (33). In addition, enhanced glycolysis and tricarboxylic acid cycle (TCA) cycle blockade in LPS-stimulated macrophages can both promote a maximal inflammatory response and terminate it later. Compared with glycolysis, IL-4-stimulated macrophages are more dependent on fatty acid oxidation (FAO) (36).

Alternately activated macrophages, M2 macrophages, are a predominantly pro-inflammatory phenotype, reduce plaque size, and enhance plaque stability (30). M2 macrophages focus on suppression of inflammation, removal of cellular debris and apoptotic cells, and promotion of tissue repair and fibrosis, hepatobiliary regeneration, matrix degradation and repair, and tissue reconstruction (33). It can be polarized by a variety of stimulatory factors, including cytokines (IL-4, IL-10, and IL-13), glucocorticoids, immune complexes (ICs), and LPS (37).

Functionally, activated M2 macrophages produce anti-inflammatory cytokines (e.g., IL-10, IL-4, TNF-β) and chemokines (e.g., CCL17, CCL22, and CCL24), thereby initiating functional anti-inflammatory regulatory mechanisms, which play an important role in suppressing inflammation and repairing damaged tissues. Among them, IL-4 type I and type II receptors activate signal transducer and activator of transcription (STAT) 6, which in turn activates the transcription of genes typical of M2 macrophage polarization (34). M2 macrophages exhibit weak capacity of lipid accumulation due to low expression of liver X receptor α (LXRα), ATP-binding cassette transporter protein 1 (ABCA1), and apolipoprotein E (ApoE). Enhanced cytokinesis in AS lesions induced by increased M2 macrophage polarization shows another role for M2, so that more M2 macrophages are required for plaque regression. M2 macrophages are classified into four subtypes, M2a, M2b, M2c, and M2d, which have different effects on AS (26).

M2a macrophage, induced by IL-4 and IL-13, has potent anti-inflammatory properties, is characterized by poor phagocytosis and inhibition of pro-inflammatory cytokine release, but is insensitive to inflammatory stimuli and is mainly involved in wound healing, tissue remodeling, and angiogenesis. Thus, M2a is less efficient than M1 in inducing antigen presentation, generating toxic oxygen and nitrogen radicals, and killing intracellular pathogens. M2a cells express high levels of mannose receptor (MR), glucocorticoid receptor (SR), and IL-10 receptor (IL-10R). Polarization of M2a results in the release of pro-fibrotic factors such as TGF-β, insulin-like growth factor (IGF), fibronectin, and inflammatory chemokines such as CCL17, CCL18, CCL22, and CCL24, which contribute to extracellular matrix deposition and contribute to tissue repair and thus have been described as “tissue repair” macrophages (38). In addition, IL-6 expression induces M2a macrophage polarization toward M1/M2b; if IL-6 is inhibited, M1/M2b macrophages are induced to polarize toward M2a, thereby controlling atherosclerotic intimal hyperplasia (39).

M2b macrophages, induced by IC, TLR agonists, and IL-1R ligands, are polarized to release high levels of CCL1, IL-6, IL-1β, TNFα, and TNF superfamily member 14 (TNFSF14). In addition, M2b macrophages express and secrete large amounts of the anti-inflammatory cytokine IL-10 and low levels of the pro-inflammatory factor IL-12, with both inhibitory and promotional effects, termed regulatory macrophages (37). M2b macrophages may inhibit AS by suppressing leukocyte infiltration, and transplanted M2b macrophages may also protect the heart from damage associated with ischemia–reperfusion (40).

M2c macrophage, in a microenvironment enriched with glucocorticoids, IL-10, TGFβ, and prostaglandins E2, are induced to polarize to become M2c macrophage by IL-10R and transcription activator 3 (TAT3) (37), which then secrete high levels of IL-10, TGF-β, and PTX3 proteins to achieve the associated inflammatory regression and tissue repair (38). Both M2b and M2c macrophages have regulatory functions in addition to being antigen-presenting cells, which are characterized by the release of the anti-inflammatory cytokine IL-10. However, both M2b and M2c macrophages have the ability to produce large quantities of pro-inflammatory cytokines, and both exhibit high expression of Mer receptor tyrosine kinase and are efficiently phagocytized, so they are also known as regulatory macrophages.

M2d macrophages represent a new subpopulation of M2 macrophage, also known as tumor-associated macrophage, induced by TLR ligands, A2 adenosine receptor agonists, and IL-6 (37). Moreover, M2d macrophages have been shown to participate in angiogenesis through the expression of vascular endothelial growth factor (VEGF) and IL-10, as well as secrete a certain amount of inducible nitric oxide synthase (iNOS), resulting in a pro-inflammatory effect (38). However, unlike the typical M2 macrophage, M2d macrophages do not express Ym1, Fizz1, or cluster of differentiation (CD) 206. Likewise, IL-10 contributes to M2d polarization and VEGF production.

In addition to macrophages of the M1 and M2 phenotypes, other polarized macrophages were observed in the plaques such as M(Hb), Mhem, Mox, and M4 (32). Comparative characteristics of macrophage subtypes are shown in Figure 3 . Mox macrophages are induced by oxidized phospholipids and ox-LDL and are characterized by reduced phagocytic activity and chemotaxis, which account for approximately 30% of the total macrophage content of atherosclerotic plaques. In addition, the expression of antioxidant enzymes in Mox macrophages was significantly upregulated by nuclear factor red lineage 2 (NRF 2)-related genes but retained the ability to release the pro-inflammatory cytokines, including IL-10, IL-1β, and cyclooxygenase (COX)-2, thereby exerting an antioxidant effect (30). This suggests that Mox macrophage may also have anti-atherosclerotic and anti-oxidative stress capabilities (41). M4 macrophages are induced to polarization by CXCL4 and express pro-inflammatory cytokines such as IL-6 and TNF-α. However, M4 macrophages express both pro-AS and anti-AS genes and lack the associated expression of CD163, thus having a dual role in AS (30, 32). The phagocytosis of M4 macrophages is inhibited, with a lower expression of scavenger receptors and a higher expression of cholesterol efflux transporter proteins, suggesting a lesser ability to form foam cells (42).

M (Hb) and Mhem macrophages differ from other macrophages in that they coexist at newly formed vessels and the site of hemorrhage in unstable plaques. Intraplaque hemorrhage promotes AS by providing cholesterol-rich erythrocyte membranes and a dual stimulus of oxidized heme and iron. M(Hb) macrophages polarized by hemoglobin (Hb) stimulation typically express high levels of MR and CD163 and are involved in the clearance of the hemoglobin/hemopexin (Hb/Hp) complex after plaque hemorrhage. Following endocytosis of the Hb/Hp complex and erythrocytes, released hemoglobin polarizes macrophages to the Mhem phenotype (42). In intraplaque hemorrhage, M(Hb) and Mhem macrophages recycle erythrocyte remnants and Hb, possibly induced by Hb, albumin, and CD163. M(Hb) macrophages release LXRα, LXRβ, and ABC transporter proteins (ABCA1 and ABCG1) responsible for cholesterol efflux. Mhem macrophages release heme oxygenase-1, which prevents foam cell formation and shows anti-atherosclerotic effects by reducing oxidative damage in plaques. In addition, M(Hb) and Mhem are equally anti-inflammatory, producing anti-inflammatory cytokines such as IL-10, thereby preventing the progression of plaque formation (32).

ASCVD is directly associated with elevated levels of LDL-C and ApoB 100, and LDL-C-containing infiltration and retention in the arterial wall are a key initiating event in AS, which triggers an inflammatory response and promotes AS (43). Since cholesterol metabolism is crucial in the pathogenesis of AS, lipid-lowering drugs have long been used as the mainstay of clinical treatment for AS, so this article is only relevant to lipid-lowering drugs. Global clinical guidelines recommend LDL-C as the primary target for lipid control, and statins are recommended as the first-line therapeutic agent for lowering LDL-C levels, in conjunction with cholesterol absorption inhibitor and proprotein convertase subtilisin kexin/type 9 (PCSK9) inhibitors, if necessary (44, 45). The mechanism of the above three classes of drugs is shown in Figure 4 . Notably, the modulatory effect of statins on inflammation (anti-inflammatory/pro-inflammatory) is somewhat controversial, and statins could induce macrophage polarization into M1-type macrophages, M2-type macrophages, or both M1 and M2, which is related to the cellular microenvironment as well as to the variability of statins (46, 47). It has been shown that monocytes and macrophages are differentially regulated by statins, with monocytes showing no change in response to statins, but macrophages differentiated in the presence of statins remain functionally responsive to inflammatory activation, retaining their monocyte function and maintaining an immune/inflammatory response state (48). In addition, PCSK9 induces pro-inflammatory macrophage activation and does not depend on the mechanism of the LDL receptor (LDL-R) (49, 50), from which it can also be inferred that PCSK9 inhibitors have some anti-inflammatory effects.

These drugs are widely used in clinical practice and have proven efficacy; however, their adverse effects should not be ignored. Adverse effects of statins include abnormalities in liver function, such as elevated transaminases and varying degrees of liver damage. Moreover, statins inhibit mitochondrial function, reduce energy production, and alter muscle protein degradation, resulting in muscle-related symptoms such as muscle pain, muscle weakness, and, in rare cases, rhabdomyolysis (51). In addition, statins have an effect on blood glucose, such as elevated blood glucose, and there is an increased risk of new-onset diabetes with long-term, high-dose statin use (52). Other studies suggest that statins may be the cause of coronary artery calcification and can act as mitochondrial toxins to impair muscle function in the heart and blood vessels (53). Cholesterol absorption inhibitors, such as ezetimibe and hybutimibe, can reduce LDL by approximately 15%–20% when used alone. This is because dietary sources of cholesterol account for 30% of the three cholesterol source pathways, have a single mechanism of action, are less effective than statins, and often need to be used in combination with statins (54). PCSK-9 inhibitors as monoclonal antibodies block PCSK-9 and reduce LDL-C, showing anti-atherosclerotic activity. However, the high cost of treatment limits their larger-scale application. Notably guidelines around the world emphasize the long-term, personalized, and preventive nature of AS drug therapy (55). Therefore, the monotypic and uniform nature of AS medication needs to be somewhat reformed.

TCM has the advantages of multicomponents and multitargets. In recent years, a number of studies have provided new ideas for the prevention and treatment of AS. In this paper, the mechanism of TCM in treating AS through the target of macrophages was explored in three TCM categories: monomer, extract, and compound. The search tool used was PubMed, and AS, Macrophages & TCM was searched in the title/abstract. The details are shown in Table 1 (herbal monomers/extracts for AS via macrophages) and Table 2 (herbal compounds for AS via macrophages). Moreover, according to the table, the mechanisms and effects of TCM medicines in treating AS were summarized, and the details are shown in Figure 6 .

Notably, TCM can inhibit the polarization of M1 macrophages and promote the activation of M2 macrophages as a means of delaying the development of AS and enhancing plaque stability. For example, in the table, the herbal monomer geniposide induced M2 polarization in plaques via upregulation of CXCL14 (80); the herbal extract Leech Peptide HE-D inhibited macrophage migratory activity and promoted macrophage transformation from M1 to M2 via the NF-κB signaling pathway (81); the herbal compound Jisil Haebaek Gyeji-Tang inhibits polarization of inflammatory M1-type macrophages by inhibiting MAPK and NF-κB signaling pathways (82); and Tanyu Tongzhi Formula promoted the activation of M2 macrophages by activating the PPARγ signaling pathway and inhibiting the AKT/ERK signaling pathway (83). Thus, macrophage polarization is closely related to cytokine–cytokine receptors, chemokine-related signaling pathways, and inflammation-related MAPK and NF-κB signaling pathways, reflecting the importance of the cellular microenvironment for macrophage polarization and function.

It has been shown that Ganoderma Lucidum Spore Ethanol Extract, via the LXRα-related pathway, can regulate lipid metabolism, in which TG and LDL-C are reduced and HDL-C is elevated, thereby inhibiting foam cell formation and also ruling out the typical adverse effects of statins, such as muscle-related symptoms and liver function abnormalities. Therefore, the targets of TCM are not limited to the reduction of LDL but also target the elevation of HDL, which serves to comprehensively regulate lipids.