Atherosclerosis is a complex process that involves the interaction between oxidized low-density lipoproteins (oxLDLs), macrophages, endothelial cells, and vascular smooth muscle cells (1). It is an inflammatory disease of the large artery driven by macrophage activation and infiltration. Through scavenger receptors, macrophages uptake oxLDLs and other lipids, leading to foam cell formation and fatty streak lesions characteristic of early atherosclerosis. The macrophage-derived foam cells frequently undergo apoptosis to give rise to cholesterol-rich necrotic cores to advance atherosclerotic lesions (2).

Ion channels, transmembrane proteins that allow the flow of ions across cell membranes, are emerging as important regulators of macrophage function (3, 4). Recent studies have revealed diverse roles of ion channels in macrophages and their implications in immune responses and inflammatory diseases, including atherosclerosis (5). In the present review, we discuss ion channel regulation of macrophage function and summarize studies in macrophage ion channel dysfunctions associated with pathogenesis of atherosclerosis.

Macrophages play a crucial role in the initiation, progression, and complications of atherosclerosis (2, 6, 7). In the presence of risk factors such as high blood pressure, dyslipidemia, diabetes, and smoking, plasma lipoproteins enter the intima by permeating through the vessel wall, where they are modified into oxidized lipoproteins including oxLDLs (8–11). This leads to the activation of endothelial cells, triggering the expression of adhesion and chemotactic factors that attract monocytes. Consequently, monocytes differentiate into macrophages and transform into foam cells in the intima.

The foam cells are formed by the uptake and accumulation of oxLDLs through scavenger receptors in macrophages, leading to the development of fatty streak lesions and atherosclerotic plaques (7). Macrophages express several scavenger receptors including SR-A1 (Scavenger Receptor - Class A1) and CD36 (i.e., SR-B2, Scavenger Receptor - Class B2). The SR-A1 binds to the modified LDL such as oxLDL and is involved in the subendothelial translocation of LDL. SR-A1 function is associated with JNK2 signal pathway, it was reported that JNK2-dependent phosphorylation of SR-A1 promotes the uptake of LDL in macrophage and enhances the foam cell formation (12). The CD36 is the predominant scavenger receptor for oxLDL, and the binding between CD36 and oxLDL triggers TLRs signaling pathway to promote pro-inflammatory responses to mediate the progression of foam cell formation and atherosclerosis (13).

Meanwhile, macrophages in atherosclerotic lesions produce various inflammatory cytokines such as IL-1β, IL-6, IL-12, IL-18, and TNF to promote smooth muscle cell proliferation and recruit other inflammatory cells (14). For example, IL-1β induces angiogenesis through the recruitment of myeloid and endothelial cells. IL-6 promotes activation of endothelial cells and induces smooth muscle cells proliferation. IL-12 stimulates the differentiation of T cells and recruits T cells into the atherosclerotic plaques. IL-18 enhances the expression of scavenger receptor CD36 to accelerate atherosclerosis. And TNF induces expression of adhesion molecules and enhances the recruitment of other inflammatory cytokines into the plaques. Taken together, these sustained inflammatory responses create an atherogenic environment, further regulating plaque progression (2).

Within the microenvironment of atherosclerotic plaques, macrophages receive various stimulation and polarize into distinct subtypes. The macrophage subtypes, including M1 and M2, play diverse roles in the advancement of atherosclerosis. The M1 macrophages secrete pro-inflammatory cytokines, contribute to plaque instability, and promote thrombosis. In contrast, M2 macrophages exhibit anti-inflammatory properties, promote tissue repair, and aid in the resolution of inflammation. Imbalances in macrophage polarization affect plaque stabilization in the development of atherosclerosis (6).

Ion channels are transmembrane proteins that enable the passage of ions across cell membranes and regulate physiological processes (15–23). Recent studies have shown ion channels regulate macrophage function (3, 4). Several ion channels in macrophages are implicated in immune responses and inflammatory diseases. The macrophage ion channels include potassium channel, transient receptor potential (TRP) channel, calcium channel, mechanosensitive Piezo channel, chloride channel, and proton channel (3–5).

Potassium channels are crucial regulators of macrophage membrane potential and ion homeostasis. Macrophages express a variety of potassium channels, including inward-rectifying potassium channels (K_ir), voltage-gated potassium channels (K_v), and Ca²⁺-activated potassium channels (K_Ca) (5, 24). These channels modulate macrophage membrane potential, calcium signaling, cytokine release, and phagocytosis. Dysregulation of potassium channels can lead to abnormal macrophage activation and cause chronic inflammation (25, 26).

TRP channels are a diverse family of cation channels that play important roles in various physiological and pathological processes (27). Several TRP channels, such as TRPA1, TRPC3, TRPM2, and TRPV4, are expressed in macrophages (5). Emerging evidence suggests their involvement in macrophage function and inflammatory responses. TRP channels have been shown to modulate macrophage M1/M2 polarization and play roles in calcium homeostasis and reactive oxygen species (ROS) production. Some TRP channels have been implicated in the formation of macrophage-derived foam cells and the development of atherosclerosis (28–34).

Macrophages also express multiple types of calcium channels, including store-operated calcium channels (SOCCs) and voltage-gated calcium channels (Ca_v) (3, 5). Calcium ions (Ca²⁺) serve as universal second messengers and play a central role in macrophage signaling. Calcium influx through the calcium channels triggers intracellular signaling cascades, leading to macrophage activation, phagocytosis, and cytokine secretion. Abnormal calcium signaling in macrophages has been associated with various inflammatory diseases (35, 36).

In addition, macrophages express chloride channels involved in cellular volume regulation and mechanosensitive Piezo1 that mediated cellular mechano-signaling. Macrophages also express proton channels regulating the activation of phagocyte NADPH oxidase to regulate the process of phagocytosis (3, 5).

In the development of atherosclerosis, macrophage ion channels play important roles in several key cellular events, such as macrophage polarization and infiltration, cell proliferation and migration, and foam cell apoptosis. Recent studies indicated that macrophage ion channels are associated with the pathogenesis of atherosclerosis ( Table 1 ).

We discuss ion channels regulation of macrophage function during the progression of atherosclerosis, as well as summarize recent studies in macrophage ion channel families associated with atherosclerosis. Macrophages are critical players in the pathogenesis of atherosclerosis, influencing multiple stages of plaque development and plaque stability. Ion channels play critical roles in macrophage biology, regulating diverse cellular processes that impact macrophage activation, polarization, phagocytosis, and cytokine secretion. Dysregulation of ion channels is implicated in macrophage-mediated atherogenesis, making them attractive targets for therapeutic intervention.

Although significant progress was made in the functional characterization of the K⁺, TRP, Ca²⁺, and Cl^- channels in the progression of atherosclerosis ( Figure 1 ), emerging evidence indicated other macrophage ion channels, such as intracellular channels and H⁺ channels, are potentially novel targets against atherosclerosis.

For example, studies have shown that ryanodine receptor 3 (RyR3) channel mutations are associated with atherosclerosis in populations (61). RyR3 is one of the ryanodine receptor channel isoforms expressed on the endoplasmic reticulum of immune cells, including macrophages (62, 63), RyR3 mutations may cause the dysfunction of the channel, which in turn, lead to abnormal calcium signaling linked with the development of atherosclerosis.

Meanwhile, accumulated evidence suggests that H_v1 proton channel is associated with atherosclerosis. H_v1 channel controls acid extrusion from cells and regulates cellular pH homeostasis (64). It is highly expressed in macrophages, and its activity promotes macrophage migration and inflammatory cytokines secretion (65, 66). The microarray data has revealed that H_v1 was remarkably upregulated during atherogenesis and downregulated along with the atherosclerotic lesion regression (67), indicating that H_v1 is linked with atherogenesis and involved in the pathological process of this disease.

Moreover, acid-sensing ion channel member 1 (ASIC1) was recently proposed to play a role in atherosclerotic development. ASIC1 channel in macrophages decreases ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux, indicating a role of macrophage ASIC1 in lipid metabolism and atherosclerosis progression (68).

Future studies are required to characterize new roles of these channels in the pathogenesis of atherosclerosis. Meanwhile, studies have shown that ion channels regulate genetic expression in various cells (69–72), it remains to determine if ion channels regulate the gene transcriptional networks controlling macrophage activation linked with atherogenesis. The investigation in this field will extend our understanding of the function of macrophage ion channels in human diseases and discover novel targets against atherosclerosis.

LH conceptualized the review. XW created the Figure and Table. XW, SS, JL, and LH wrote and edited the manuscript. All authors contributed to the article and approved the submitted version.