The bone marrow produces monocytes, which are transient blood cells. While in blood vessels, they have the ability to release inflammatory cytokines and change into long-lived macrophages. The functions that various macrophage subtypes perform in the development of plaque vary. When intima-resident macrophages consume more lipids and generate foam cells, plaques start to grow. Plaques require ongoing blood flow and a monocyte inflow to progress, which encourages the development of plaque macrophages [8].

The ability to precisely react to triggers in the local microenvironment to either eliminate or prolong inflammation is one of the traits that sets macrophages apart [9]. Macrophage morphologies are classified into two groups (M1 and M2) based on cytokine-induced in vitro characteristics. The production of pro-inflammatory cytokines and host defense depend on M1 macrophages, which are pro-inflammatory macrophages. M2 macrophages have been shown to lower inflammation and promote tissue repair [10]. Both traditionally and alternatively activated subgroups of macrophages have been found to adhere to plaque in both human and murine atherosclerotic lesions. Prolonged inflammation triggers macrophage mortality and, in the absence of efficient efferocytosis, leads to the buildup of apoptotic cells and debris, which facilitates the formation of a necrotic plaque core. M2 macrophage- representing cells are located in stable plaque locations in human diseases, whereas proinflammatory marker- expressing macrophages are observed in unsteady, rupture-prone places [11].

The most prevalent type of leucocytes is neutrophils, which release a number of inflammatory mediators, including pentraxin 3, matrix metalloproteinases (MMPs), reactive oxygen species, and myeloperoxidases (MPOs). Pentraxin 3 stimulates the activation of complement and leukocyte adherence by binding to C1q. Cathelicidin is secreted by triggered neutrophils. It promotes the adhesion of monocytes and other myeloid cells either directly or through receptor binding. The azurophilic, particular, gelatinase, and secretory granules that are found inside neutrophils and developed during their development are all known to exacerbate atherosclerosis. Proteasessuch as gelatinase (MMP-9) and MMP-25, which are found in azurophilic granules, break down the extracellular matrix and encourage the lysis of the fibrous plaque cap [12]. Type IV collagen, which is essential to the endothelial cell membrane, is broken down by MMP-9 in conjunction with MMP-2. Defensins found in azurophilic granuleslinked to dysfunction of endothelial cells, chemokine attraction, and deprived cholesterol utilization are also releasedby neutrophils [13].

In the early phases of atherosclerosis, T lymphocytes, monocytes, and macrophages are the first cells to be attracted. The same chemokines that cause monocyte adherence also drive T lymphocyte recruitment. Depending on whether they are CD4 + or CD8 + T cells, all T cells express CD3 +, the T cell receptor (TCR) complex, and other co-receptors. Atherosclerosis is mainly triggered by CD4 + T cells, which are the source of T helper cells differentiation. Several Th subtypes (Th1, Th2, Th9, Th17, Th22, follicular helper T cells (TFH), and CD28 + T cells) or Treg subtypes develop from CD4 + T cells after antigen presentation [14]. Th1 and Th2 subgroups prevail in the atherosclerotic plaque, Th1 is the predominant type with a demonstrated atheroprotective effect. The influence of other lymphocyte types such as Th2, Th9, Th17 and Th22 has not been fully recognized [14]. CD44, a signaling marker that separates naive T cells from memory cells and effector counterparts, is one of the markers displayed on T cells that shows the clonal formation of these cells upon contact with antigens. It also plays a significant role in infarct recovery. Mice lacking CD44 exhibited enhanced leukocyte adherence to the infarct zone with noticeable collagen deposition, as well as extended production of inflammatory cytokines. CD4 + T cells, which function as autoantigens with the activation of the adaptive immune system, can be activated by antigens such as LDL cholesterol and apolipoprotein B [15].

Both normal and diseased arteries contain B cells, which are crucial components in atherosclerosis. While follicular B cells and innate triggers of B cell activation have been demonstrated to encourage atherosclerosis by inducing the Th1 adaptive immune system, B1 and marginal zone B cells are believed to offer defense against atherosclerosis [16]. Inflammatory events promote the aggregation of B lymphocytes and the development of arterial tertiary lymphoid tissue when B cells are recruited to the vascular adventitial microenvironment. These lymphoid organs include a much smaller proportion of CD19 + CD11b– and CD19 + CD11b+ B cells, which are the two main kinds of B cells. By inhibiting T cell responses, the latter B cell subtype seems to have protective benefits [17]. Three primary methods are used by B cells to induce atherogenesis: cytokine release, immunoglobulin synthesis, and antigen presentation. The immune response in atherosclerosis is counterbalanced by the production of antigen- specific antibodies, which activate a range of cells by binding to the FcR receptor, neutralizing oxidized lipoproteins, and initiating the complement pathway. Through costimulatory markers including CD40, CD86, CD80, or MHC-II, B lymphocytes and Th cell lymphocytes engage in arterial tertiary lymphoid tissue [18]. The effector activity of T cells is ensured by this contact between B and T cells. Research demonstrates the presence of plasma cells that secrete anti-LDL immunoglobulins targeting oxidation-specific epitopes, which trigger protective antibodies and reduce plaque. The fact that B cells carry the B cell receptor (BCR) antigen and TLRs implicated in both innate and adaptive responses at the same time, however, makes studying B cells in atherosclerosis much more challenging. By boosting inflammatory cytokines and chemokines, stimulation of the TLR in atherosclerosis encourages the formation of plaque [19]. It is unclear exactly which endogenous or foreign antigens activate BCR and/or TLRs. Additionally, B lymphocytes release cytokines that either delay the development of atherosclerotic plaque (IL-2, IL-4, IL-10) or induce it (tumor necrosis factor-alpha (TNF-$\alpha$), INF-$\gamma$). While effector B2 cells produce IL-2, IL-4, and TNF-$\alpha$, effector B1 cells express TNF-$\alpha$, INF-$\gamma$, and IL-12 [20].

While macrophages, neutrophils, T cells, and B cells each contribute distinct functions to atherosclerotic progression as outlined above, mast cells represent a unique immune cell population that combines and amplifies many of these individual functions. Unlike other immune cells that typically exhibit specialized roles, mast cells serve as multifunctional orchestrators capable of simultaneously promoting lipid accumulation, enhancing inflammatory cell recruitment, mediating matrix degradation, and driving plaque destabilization through their diverse secretory profile. This multifaceted nature, combined with their strategic tissue localization and rapid response capabilities, positions mast cells as particularly significant contributors to atherosclerotic pathogenesis, justifying their dedicated examination in the following sections.

Mast cells are recognized as key promoters of angiogenesis [21]. They secrete numerous pro-angiogenic mediators, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGF-$\beta$), tumor necrosis factor-alpha (TNF-$\alpha$), and interleukin-8 (IL-8). Additionally, they release heparin and proteases that facilitate the storage and stabilization of these growth factors. Histamine released by mast cells increases microvascular permeability, further supporting neovascularization. Notably, mast cell-driven angiogenesis has also been observed in the context of tumor progression [21].

Mast cells play a pivotal role in maintaining immune homeostasis. Due to their strategic localization in the skin and mucosal surfaces, they act as frontline defenders against external antigens [22]. They are particularly important in preserving the equilibrium of intestinal microbiota [23]. Given the constant exposure of the gastrointestinal tract to microbial and dietary antigens, epithelial barriers require immune support. Mast cells, via ATP-mediated signaling, facilitate the differentiation of follicular helper T cells, thereby contributing to IgA production and microbial homeostasis in the gut [23].

Mast cells are integral to both innate and adaptive immune responses. They can detect pathogenic stimuli through direct interaction with microbes or by recognizing pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors such as Toll-like receptors (TLRs) and complement receptors [24]. Upon engagement with specific antigens, mast cells initiate the release of inflammatory mediators aimed at pathogen clearance. The nature of the immune response depends on the specific TLR involved. For instance, activation of TLR2 by Gram-positive bacteria or mycobacteria leads to IL-4 secretion, whereas TLR4 engagement by lipopolysaccharides from Gram- negative bacteria induces the release of pro-inflammatory cytokines (e.g., TNF-$\alpha$, IL-1, IL-6) without degranulation [24]. Conversely, peptidoglycan from Gram-positive bacteria can trigger mast cell degranulation and histamine release via TLR2 activation [25].

Mast cells support bacterial elimination by increasing vascular permeability, promoting edema, and recruiting immune effector cells such as eosinophils, neutrophils, and natural killer (NK) cells. They also directly produce antimicrobial peptides including cathelicidins, defensins, and psidins. In antiviral defense, mast cells enhance cytotoxic responses by recruiting CD8+ T cells and promoting the release of type I interferons (IFN-$\alpha$, IFN-$\beta$) [26]. One of the earliest recognized roles of mast cells involves defense against parasitic infections through IgE-mediated mechanisms. The release of mediators such as histamine increases smooth muscle contraction and vascular leakage, facilitating the expulsion of parasites via vomiting, diarrhea, or coughing [27].

In the context of adaptive immunity, mast cells are capable of processing and presenting antigens via MHC class I and II molecules [28]. They also activate dendritic cells, which serve as critical antigen-presenting cells. Upon stimulation through Toll-like receptor 7 (TLR7), mast cells secrete IL-1 and TNF-$\alpha$, thereby promoting dendritic cell migration from peripheral tissues to regional lymph nodes, where they activate cytotoxic T lymphocytes. Moreover, mast cells can directly enhance T cell cytotoxicity through TNF-$\alpha$ secretion [25].

Mast cells contribute to early atherogenesis by facilitating the infiltration of low-density lipoprotein (LDL) particles into the arterial intima. Histamine, acting through H1 receptors on endothelial cells, increases vascular permeability, enhancing LDL entry and promoting plaque formation in hypercholesterolemic models [29]. Despite mast cells being primary sources of histamine, other cells, such as endothelial cells also produce it, implying that not all histamine-driven effects are mast cell-specific. Exceptions include unique mast cell mediators like heparin and tryptase. Tryptase, for instance, can compromise the endothelial barrier to LDL via activation of protease-activated receptor-2 (PAR-2) [29].

Activated mast cells also release chemokines that attract monocytes and stimulate endothelial cells to express adhesion molecules, further promoting monocyte transmigration into the subendothelial space [30]. In vitro, chymase from mast cells has been shown to cleave the C-terminal region of apolipoprotein A-I (apoA-I), impairing its anti- inflammatory properties. Truncated apoA-I fails to inhibit TNF-$\alpha$-induced adhesion molecule expression in coronary endothelial cells. Thus, mast cells in the subendothelium, via secretion of TNF-$\alpha$, chemokines, and proteases, facilitate monocyte recruitment to atherosclerotic regions [31].

Within the intima, heparin-containing mast cell granules bind to apoB-100 on LDL via electrostatic interactions. Chymase then proteolytically modifies apoB-100, destabilizing LDL particles and promoting their aggregation into larger complexes akin to those observed in atherosclerotic lesions. This aggregation increases cholesterol accumulation within the plaque [32].

Histamine increases endothelial permeability to High-Density Lipoprotein (HDL) particles. Pre$\beta$-HDL particles normally facilitate efficient reverse cholesterol transport from foam cells. However, these particles are susceptible to degradation by mast cell proteases tryptase and chymase. This degradation reduces their cholesterol efflux capacity. Therefore, mast cell activation promotes foam cell formation through two mechanisms: increased LDL uptake and impaired HDL-mediated cholesterol removal [33, 34].

Continual LDL influx and foam cell formation, compounded by inadequate cholesterol efflux to dysfunctional HDL, lead to macrophage retention and eventual cell death within the plaque [35]. Mast cell-derived histamine can trigger macrophage apoptosis, contributing to necrotic core expansion and plaque enlargement [36].

As atherosclerotic plaques enlarge and reduce arterial lumen diameter, disturbed blood flow induces endothelial dysfunction and detachment. Mast cells residing beneath the endothelium may release tryptase and chymase, which degrade the basement membrane and promote endothelial cell apoptosis, exacerbated by TNF-$\alpha$ secretion [37]. IL-8 released from mast cells can recruit neutrophils, which further damage endothelial cells from the luminal side, enhancing thrombus development [38, 39].

Thinning of the fibrous cap is a critical event in plaque vulnerability. It is driven by diminished collagen synthesis due to smooth muscle cell senescence and apoptosis, and by increased matrix degradation via metalloproteinases (MMPs) [40]. Chymase induces apoptosis in smooth muscle cells by degrading fibronectin and inhibits collagen synthesis through both TGF-$\beta$-dependent and independent mechanisms. Moreover, chymase and tryptase can activate pro-MMP-1 and pro-MMP-3, contributing to collagen breakdown [41, 42]. Elevated MMP activity and mast cell degranulation have been observed in rupture-prone plaque regions, suggesting a direct role of mast cells in fibrous cap destabilization [43].

Mast cells serve as crucial orchestrators of inflammatory cascades in atherosclerotic plaques through complex interactions with multiple immune cell populations [21]. Upon activation by oxidized LDL or complement components, mast cells release a diverse array of inflammatory mediators, including leukotrienes, prostaglandins, and platelet-activating factor, which collectively amplify the local inflammatory response [44]. These lipid mediators promote additional recruitment of inflammatory cells, including T lymphocytes and dendritic cells, establishing a self-perpetuating cycle of inflammation [45]. Mast cell-derived IL-6 and IL-1$\beta$ further enhance T helper cell differentiation toward pro-atherogenic Th1 and Th17 phenotypes, while simultaneously suppressing regulatory T cell function through direct cytotoxic effects [46]. Additionally, mast cells can present antigens to T cells via MHC class II molecules, directly participating in adaptive immune responses within the atherosclerotic microenvironment [47]. The interaction between mast cells and neutrophils is particularly significant, as mast cell-derived chemokines promote neutrophil extracellular trap (NET) formation, which contributes to endothelial damage and thrombosis risk [48].

Recent evidence demonstrates that mast cells contribute to atherosclerosis progression through metabolic reprogramming of the plaque microenvironment and enhancement of oxidative stress pathways [49]. Activated mast cells undergo glycolytic reprogramming, leading to increased lactate production and local acidification of the atherosclerotic milieu. It impairs endothelial function and promotes smooth muscle cell proliferation [50]. Mast cell-derived reactive oxygen species (ROS), particularly superoxide and hydrogen peroxide, directly oxidize LDL particles within the plaque, creating highly atherogenic oxidized LDL that is preferentially taken up by macrophages [51]. Furthermore, mast cells secrete myeloperoxidase, which catalyzes the formation of hypochlorous acid and chlorotyrosine-modified proteins, contributing to endothelial dysfunction and plaque instability [52]. The release of histamine also upregulates NADPH oxidase expression in vascular smooth muscle cells, perpetuating ROS production and promoting a pro-oxidant environment [53]. Mast cell granules contain significant amounts of heparin sulfate proteoglycans, which can bind and concentrate oxidized phospholipids, creating localized zones of enhanced oxidative stress that accelerate atherosclerotic progression [54]. This metabolic dysregulation extends to cholesterol homeostasis, as mast cell-derived enzymes can interfere with ATP-binding cassette transporter function, further impairing reverse cholesterol transport [55].

Mast cells undergo metabolic shifts similar to those observed in tumor-associated macrophages, characterized by enhanced glycolytic activity that drives lactate production and creates an acidic microenvironment that promotes inflammatory mediator release [50]. This metabolic reprogramming not only affects mast cell function but also influences neighboring immune cells. The lactate produced by glycolytically active mast cells can directly impact macrophage polarization, promoting their differentiation toward the pro-inflammatory M1 phenotype while simultaneously enhancing foam cell formation.

Furthermore, mast cell-derived reactive oxygen species (ROS) directly impact macrophage lipid metabolism by promoting lipid peroxidation and enhancing the uptake of oxidized LDL, thereby accelerating foam cell formation [51]. The cross-regulation extends to T cell metabolism, where mast cell-derived inflammatory mediators can influence T helper cell differentiation and metabolic programming, creating a self-perpetuating cycle of metabolic dysfunction and immune activation.

These findings illustrate how mast cell metabolic changes create a complex network of metabolic and immunological interactions that synergize to drive immune dysregulation in atherosclerosis, representing potential targets for therapeutic intervention.

A summary diagram of the role of mast cells in atherosclerosis is presented in Fig. 1.

Fig. 1.

Scheme of the influence of mast cells on the pathogenesis of atherosclerosis. This schematic diagram illustrates the multifaceted role of mast cells in atherosclerosis pathogenesis. (1) Early atherogenic events show mast cells releasing histamine that increases endothelial permeability, allowing LDL infiltration into the arterial wall. (2) Mast cell-derived tryptase and chymase promote LDL aggregation and foam cell formation while degrading protective HDL particles. (3) Inflammatory mediator release (TNF-$\alpha$, IL-6, IL-1$\beta$) attracts monocytes and other immune cells to the developing plaque. (4) Advanced plaque progression involves mast cell-mediated smooth muscle cell apoptosis and extracellular matrix degradation through MMP activation. (5) Fibrous cap thinning occurs through chymase-mediated collagen breakdown and tryptase activation of proteolytic enzymes. (6) Metabolic reprogramming leads to increased oxidative stress and ROS production, further destabilizing the plaque. (7) The culmination of these processes results in plaque rupture and acute cardiovascular events. Red arrows indicate pro- atherogenic pathways, while the cellular interactions demonstrate the complex network of mast cell- mediated inflammatory responses within the atherosclerotic microenvironment. PAR-2, protease-activated receptor-2; LDL, low-density lipoprotein; TNF-$\alpha$, tumor necrosis factor-alpha; IL-, interleukin-; MMP, matrix metalloproteinase; ROS, reactive oxygen species; NET, neutrophil extracellular trap; Treg, Regulatory T cells; HDL, High-Density Lipoprotein; PAF, Platelet-Activating Factor.

Some medications that particularly target human mast cell stimulation or IgE have been developed or introduced in recent years. Immunoglobulin E with Fc Epsilon Receptor I (IgE–Fc$\epsilon$RI) connection on mast cells is inhibited by omalizumab, a monoclonal antibody that binds to free IgE [64]. When this medication was given in vivo to two mice heart failure models, it reduced cardiac dysfunction and restructuring. Omalizumab has more recently been shown to prevent AngII-induced vascular remodeling and elevated blood pressure in mice [59]. These findings suggest that medications that specifically target mast cell IgE-Fc̛RI activity may considerably reduce cardiac fibrosis. Recent clinical evidence suggests that omalizumab may provide cardiovascular benefits in patients with comorbid asthma and cardiovascular disease [64]. A study [63] demonstrated that biologics targeting IgE pathways, including omalizumab, showed promise in reducing systemic inflammation markers associated with cardiovascular risk. Furthermore, clinical observations in patients treated with omalizumab for allergic asthma have reported improvements in endothelial function and reduced markers of vascular inflammation.

These clinical insights highlight the therapeutic promise of anti-IgE approaches for atherosclerosis and related cardiovascular disorders, moving beyond the preclinical evidence to demonstrate real-world potential. However, dedicated cardiovascular outcome trials specifically designed to evaluate omalizumab’s efficacy in atherosclerotic disease prevention are still needed to establish definitive clinical recommendations. Human mast cell-mediated diseases are presently being studied with lidalizumab, a second-generation humanized anti-IgE monoclonal antibody showing a greater affinity for IgE [67].

For the treatment of human diseases mediated by mast cells, a number of novel medication types that have the ability to decrease tissue mast cells population are very desirable. Furthermore, by focusing on intracellular signaling pathways such as spleen tyrosine kinase (SYK), bruton tyrosine kinase (BTK), and janus kinase (JAK), a number of promising small molecular weight drugs have been demonstrated to prevent mast cell stimulation [68]. Mast cell degranulation is inhibited by SYK inhibitors and aerosolized SYK antisense oligodeoxynucleotides. Leukotriene emission from mast cells is likewise inhibited by SYK inhibitors [69].

Mast cells include a number of inhibitory receptors, including Siglec-8, Siglec-6, CD200R, CD300a, and FcRIIb, which may be targets for atherosclerosis treatment. In humanized mice, anti-Siglec-8 antibody inhibited anaphylaxis and human mast cell activity that was dependent on IgE and non-IgE [70]. A humanized monoclonal antibody against Siglec-8 called lentelimab has demonstrated encouraging outcomes in a number of illnesses mediated by mast cells. Lirentelimab decreased the quantity of tissue mast cells [71].

Recent advances in understanding mast cell-specific proteases have opened new therapeutic avenues for atherosclerosis management through targeted enzyme inhibition [72]. Chymase inhibitors, such as chymostatin and TEI-F00806, have demonstrated significant potential in reducing plaque progression by preventing collagen degradation and smooth muscle cell apoptosis in experimental models [73]. These compounds specifically target the chymotrypsin-like activity responsible for angiotensin II formation and fibronectin cleavage, thereby preserving fibrous cap integrity [74]. Tryptase inhibitors, including nafamostat mesylate and APC 366, have shown efficacy in reducing endothelial permeability and preventing LDL infiltration into the arterial wall [75]. Additionally, dual protease inhibitors that simultaneously target both chymase and tryptase are being developed to provide comprehensive protection against mast cell-mediated plaque destabilization [76]. The metabolic reprogramming of mast cells in atherosclerotic environments has also emerged as a therapeutic target, with glycolysis inhibitors such as 2-deoxyglucose showing promise in reducing mast cell activation and inflammatory mediator release [77]. Furthermore, targeting mast cell-derived myeloperoxidase through specific inhibitors like 4-aminobenzoic acid hydrazide (4-ABAH) has demonstrated potential in reducing oxidative stress and LDL oxidation within atherosclerotic plaques [78].

The heterogeneity of mast cell populations and their diverse roles in atherosclerosis progression necessitate personalized therapeutic approaches based on individual patient characteristics and disease stage [79]. Combination therapies targeting multiple mast cell pathways simultaneously have shown enhanced efficacy compared to single- agent approaches in preclinical studies [80]. The co-administration of histamine receptor antagonists (H1 and H2 blockers) with protease inhibitors has demonstrated synergistic effects in reducing both acute inflammatory responses and chronic plaque progression [81]. Novel therapeutic combinations include the use of omalizumab with JAK inhibitors to simultaneously block IgE-mediated activation and cytokine signaling pathways [82]. Precision medicine approaches utilizing mast cell phenotyping and functional assessment are being developed to identify patients most likely to benefit from specific mast cell-targeted interventions [83]. Biomarker-guided therapy based on serum tryptase levels, chymase activity, and specific mast cell-derived cytokine profiles is emerging as a strategy to optimize treatment selection and monitoring [84]. Additionally, the development of nanoparticle-based drug delivery systems specifically targeting mast cells within atherosclerotic plaques offers the potential for localized therapy with reduced systemic side effects [85]. These targeted nanocarriers can be engineered to respond to the specific microenvironmental conditions within plaques, such as low pH and high protease activity, ensuring selective drug release at sites of mast cell accumulation [86].

Potential mast cell-targeted therapeutic strategies for atherosclerosis are summarized in (Table 1A, Ref. [59, 60, 63, 64, 65, 75]; Table 1B, Ref. [62, 63, 66, 67, 68, 69]; Table 1C, Ref. [62, 70, 71, 74, 75, 76, 77, 78, 79]).