Typically, the building blocks of atherosclerotic plaque are lipids, particularly low-density lipoprotein (LDLs), and leukocytes, especially monocytes. Initiation of atherosclerosis begins with aberrant endothelial cells coupled with augmented expression of surface adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin. Concomitantly, it was enhanced by proinflammatory cytokines and LDLs which promote monocytes infiltration into the tunica intima layer of blood vessels. LDLs are susceptible to oxidation due to enzymatic modification by lipoxygenases and myeloperoxidase or reactive oxygen species (ROS). The oxidized low-density lipoproteins (oxLDLs) are a damage-associated molecular pattern (DAMP) which are recognized by immune cells and activate the NFκB pathway to signal pro-inflammatory cytokines release including IL-1, TNF-α, and adhesion molecules (VCAM-1, E-selectin and ICAM-I) [4]. In addition, low shear stress contributed to turbulent blood flow as senescent endothelial cells diminish nitric oxide (NO) production, hence it fails to vasodilate the blood vessels [5]. With all stated conditions, endothelial cells and smooth muscle cells are activated and release monocyte-colony stimulating factors (M-CSF) that transform monocytes into macrophages. Macrophages engulf the oxLDL and transform into foam cells. The advancement of inflammation is reinforced with proinflammatory cytokines secreted by polymorphonuclear cells (PMN) including tumor necrosis alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8) and interferon (IFN)-γ [6]. Platelet-derived growth factor (PDGF) acts as a mitogen for vascular smooth muscle cells (VSMCs) to proliferate and collagen production to build fibrous cap and encompass lipid core during the initial stage. In later stages of lesion progression, pre-existing inflammation is further amplified by the aging of VSMCs with a necrotic core composed of cell debris and lipids enveloped within the fibrous cap. Eventually, VSMCs undergo apoptosis with significant fibrous cap thinning due to the degradation of collagen and extracellular matrix [7]. As a result of that, the atherosclerotic plaques lose their stability and rupture, causing platelet aggregation or even advancing to detrimental complications such as thrombosis [8].

Monocytes and macrophages are vital in the formation of atherosclerotic plaque. Both TNF-α and IFN-γ are potent proinflammatory cytokines secreted by macrophages, natural killer (NK) cells, and T-cells. IL-12 and IL-18 have distinct functions in promoting IFN-γ gene transcription in primary human CD4⁺ T cells. It was indicated that both AP-1 and STAT4 activations are needed for IL-12-dependent IFN-γ promoter activation, while IL-18 enhanced the AP-1 binding activity. Surprisingly, the synergy between IL-12 and IL-18 greatly enriched the IFN-γ production of CD4⁺ T cells. The combined effect of both cytokines enhanced the AP-1 binding activity by 20-fold, but not by IL-12 administration alone [9,10,11]. In addition, IFN-γ also triggers macrophages and monocyte to secrete ROS thus leading to cellular oxidative stress. Simultaneously, monocyte chemoattractant protein-1 (MCP-1) is also secreted to attract other macrophages and metalloproteinases to disintegrate the fibrous cap of atherosclerotic plaque [12]. Neopterin [13] and IL-12 [14] are highly expressed in atherosclerotic plaque, which could be remarkable biomarkers for atherosclerosis and CVD detection. As atherosclerotic plaque progresses, neopterin expression is intensified considerably. A stable coronary artery disease (CAD) patient and a non-CAD patient showed minimal neopterin expression in their normal and non-stenotic coronary arteries. On the other hand, neopterin expression was demonstrated to heightened in both early and advanced atherosclerotic plaques and macrophage foam cells in the coronary arteries of stable and unstable CAD patients [13]. Young apoE-deficient mice injected with IL-12 daily exhibited higher levels of antioxidized LDL antibodies and more rapid atherosclerosis than controls injected with PBS only [15]. Nevertheless, targeting the gene encoding IL-12 or vaccines against IL-12 hinders early lesion development through plaque stabilization but is not shown in late lesions [16,17].

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) in the cell-mediated immune response through upregulated-surface receptors that act as co-receptors in naïve T-cells activation with respective co-stimulatory molecules including major histocompatibility complex MHC I or II. OxLDLs are turned into foam cells through exophagy by mature DCs, which contribute to atherosclerotic plaque formation. The cells create a seal zone coupled with acidification and lysosomal secretion in the contact zone [18]. MyD88 gene is essential in the maturation of DCs through increased antigen-presenting ability and T-cells activation. Mature DCs induced the production of pro-inflammatory cytokines IFN-α and IFN-β, and chemotactic factors CCR5 and CCL5 are upregulated to exacerbate local inflammation by attracting monocytes and T-cells in atherosclerotic lesions [19]. Furthermore, DCs in aortic walls increase the production of TNF-α, IFN-γ, and collagenases MMP to degrade surrounding collagen and extracellular matrix and destabilize the fibrous cap [20].

T-cells consist of Th1, Th2, Th17, helper T cells, cytotoxic T-cells, and regulatory T-cells (T reg). They exert both proatherogenic and anti-atherosclerotic effects. In early lesions, the amount of CD8⁺ T cells is little compared to later lesions. Research showed that CD8⁺ T cells have been shifted into the dominant type in later lesions [21]. The synergistic effect of IL-12 and IL-18 on IFN-γ secretion assists in the recruitment of macrophages and differentiation of naive T cells into cytotoxic cells. Macrophages produce MMPs that degrade extracellular matrix while cytotoxic T-cells are equipped with perforin to induce pore formation coupled with granzyme B to activate caspase which led to apoptosis in VSMCs. The synergistic effect of macrophages with cytotoxic T cells is sufficiently potent to disintegrate the fibrous cap. On contrary, Th2 cells act as modulators by negating the production of IFN-γ through the secretion of anti-inflammatory cytokines such as IL-4, IL-5, and IL-13 [22]. IL-4 and IL-13 suppress monocyte activities by impeding the production of inflammatory cytokines, IL-6, TNF-α, and IL-12 [23] and by rendering the secretion of IL-1R antagonists [24]. Although IL-4 and IL-13 are anti-inflammatory in nature, but they also significantly increase the expression of VCAM-1 on the surface of vascular endothelial cells, causing T-cells to adhere to them [25] to facilitate neovascularization [26]. In endothelial cells, IL-4 and IL-13 induce the synthesis of monocyte chemoattractant protein-1 [27], and both HUVEC and dermal microvascular endothelial cells respond to IL-13 [28]. In addition, the release of TNF-α and IL-4 can induce apoptosis of endothelial cells [29]. The profound cytokines from T reg cells are anti-inflammatory cytokines, IL-10 and TGF-β. IL-10 downregulated the expression of IFN-γ, henceforth refraining from monocyte or macrophage activation, releasing cytokine and the upregulation of costimulatory molecules [30,31]. Whereas TGF-β1 was shown to repress the stimulation of IL-1β and TNF-α induced VCAM-1 expression, thus eliciting an athero-protective effect [32,33].

B-cells are complementary to T-cells, having both pro-atherogenic and anti-atherosclerotic properties. There are two major subsets of B-cells, which include B1 cells and B2 cells. B1 cell subtypes are further divided into B1-a and B-1b cells. Both subtypes are considered athero-protective by activation of the humoral response against the presence of oxLDL to produce anti-oxLDL IgM antibodies. B1-derived IgM binds to epitopes on apoptotic cells, enabling them to be cleared more efficiently and reduce the inflammation [34] with the assistance of IL-5 which allows proper expansion and releasing antibodies to prevent foam cell formation [35]. However, derived-1a-derived innate response activator (IRA) releases granulocyte-macrophage colony-stimulating factor (GM-CSF) that acts as mitogen of Ly6Chi monocytes, thus aggravating atherosclerosis by inflammatory response [36,37]. A study has demonstrated that mice deficient in IRA B cells are secured against atherosclerosis [38]. In turn, B2 cells will further differentiate into marginal zone B MZ-B cells and follicular B Fol-B cells. Fol-B cells are the predominant B2 population that produces atherogenic IgG that triggers MHC-II expression, therefore recruiting CD4⁺ T cells as well as upregulation of proinflammatory cytokines TNF-α, IL-1β, and chemokines MCP-1, henceforth exacerbating atherosclerosis [39]. Furthermore, it has been shown that Fol-B cells promote Th1 and secrete proinflammatory cytokines [40,41]. T follicular helper cells activate Fol-B cells, which differentiate into germinal center B (GC-B) cells that create GCs [40,41]. As a result of GC-B cells proliferation and affinity maturation, high-affinity antigen-specific IgG and IgE are produced [42]. It has been documented that Fol-B cells are proatherogenic, mainly by secretion of IgG and activating Th1 cells [40,41]. Moreover, the role of MZ-B cells and regulatory B cells in atherosclerosis remains obscure [39].

3. Immunosenescence in Atherosclerosis