Monocytes and macrophages are the dominant innate effectors in early atherogenesis ( Figure 2 ). oxLDL-induced endothelial activation upregulates VCAM-1 and ICAM-1, facilitating monocyte adhesion and transendothelial transmigration (36). Intimal monocytes differentiate into macrophages that internalize oxLDL via scavenger receptors (e.g., CD36, LOX-1), forming lipid-laden foam cells, which is a process amplified by pro-inflammatory cytokines such as IL-1β and TNF-α (37, 38). This process amplifies local inflammation and recruiting additional immune cells and destabilizes the plaque microenvironment. In parallel, macrophages-derived ROS, contributes to matrix degradation and promote necrotic core formation (39).

Dendritic cells (DCs) are another critical innate immune cell type, functioning as antigen-presenting cells (APCs) that process and present oxLDL-derived antigens to T cells (40, 41). Both conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs) are involved in AS by promoting antigen-specific T cell activation, pro-inflammatory responses, and loss of tolerance (42, 43). The maturation of plaque DCs, driven by inflammatory stimuli and necrotic signals, contributes to atherogenesis through enhanced T cell activation and reduced anti-inflammatory signaling ( Figure 2 ) (44, 45).

CD4+ T cell subsets play divergent roles in atherogenesis: Th1 cells secrete IFN-γ to sustain macrophage activation, whereas Th17-derived IL-17 promotes endothelial dysfunction ( Figure 2 ) (46, 47). Regulatory T cells (Tregs) counterbalance inflammation via the production of interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), yet their stability and function are impaired in the inflammatory plaque milieu due to oxLDL-induced endoplasmic reticulum stress and IL-6-mediated suppression of FoxP3 expression (48, 49).

B cells also contribute to plaque dynamics in a subset-specific manner. B2 cells exacerbate atherosclerosis through the production of IgG antibodies that that engage Fcγ receptors on macrophages, enhancing macrophage lipid uptake and inflammatory activation, while B1 cells produce IgM antibodies that facilitate apoptotic cell clearance and neutralize modified lipids, conferring atheroprotective effects (50, 51).

The SNS and PNS represent the major autonomic branches regulating immune homeostasis.

The SNS modulates immune responses primarily through the release of norepinephrine (NE) from postganglionic fibers innervating lymphoid organs, including bone marrow, spleen, and lymph nodes. NE binds to β2-adrenergic receptors (β2-ARs) expressed on various immune cells (52). In macrophages, β2-AR activation suppresses pro-inflammatory cytokines and promotes anti-inflammatory IL-10 production, shifting them toward an M2-like phenotype (53). In CD4⁺ T cells, NE signaling enhances differentiation toward Th2 and Treg subsets, while dampening Th1/Th17 responses and inflammatory cytokine release (54).

Conversely, the PNS, primarily via the vagus nerve, exerts anti-inflammatory control through the cholinergic anti-inflammatory pathway. Acetylcholine (ACh), the primary neurotransmitter of the vagus nerve, binds to α7 nicotinic acetylcholine receptors (α7nAChR) on innate immune cells, particularly macrophages and dendritic cells, or potentially at upstream autonomic ganglia such as the celiac ganglion, as suggested by recent work (11). While α7nAChR signaling can downregulate TNF-α and IL-1β and enhance IL-10 production (55), the precise anatomical locus of this modulation remains incompletely defined and may vary across inflammatory contexts.

In parallel, vagal afferent fibers can detect peripheral inflammatory mediators, such as IL-1β and TNF-α, and relay these signals to the nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV), thereby initiating a reflexive efferent anti-inflammatory output that constrains systemic immune activation (56).

Together, these autonomic circuits calibrate immune surveillance and tolerance in steady-state conditions, allowing the body to rapidly respond to threats while preventing excessive inflammation.

Beyond NE and ACh, a range of classical neurotransmitters and neuropeptides act as immune modulators.

Dopamine (DA) modulates both innate and adaptive immune responses. D1-like receptor signaling has been linked to enhanced T cell activation and pro-inflammatory cytokine release, whereas D2-like receptor activity promotes the generation and function of Tregs, thus maintaining immune homeostasis (57, 58). In APCs, DA regulates IL-12 and IL-23 expression in a receptor-dependent manner: activation of D1-like receptors, particularly D5R, enhances IL-12 and IL-23 production (via STAT3 inhibition), whereas absence of D5R markedly reduces these cytokines, illustrating how receptor subtype and local concentration shape APC-driven adaptive immunity (59).

Serotonin (5-HT), derived from both platelets and enterochromaffin cells, regulates dendritic cell maturation, macrophage chemotaxis, and T cell polarization. It exerts its effects through multiple 5-HT receptor subtypes, which are differentially expressed across immune cell types (60, 61). Serotonin signaling is also implicated in modulating vascular permeability and platelet aggregation, thereby linking neuroimmune signaling with early inflammatory responses (62, 63).

Gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the CNS, also modulates immune responses. GABA A and GABA B receptors are expressed on T cells and macrophages (64). GABAergic signaling suppresses pro-inflammatory cytokine production, inhibits antigen presentation, and promotes regulatory T cell responses. GABA analogs and receptor agonists are currently under investigation for their potential to modulate neuroinflammation and peripheral immune responses in chronic inflammatory diseases (64–66). Together, these neurotransmitters form a regulatory axis that enables context-dependent modulation of immune function across peripheral and central compartments.

NICIs have recently been identified as specialized sites in the adventitia of large arteries, including the aorta and carotids. These interfaces consist of sensory afferents, sympathetic nerve fibers, resident immune cell clusters (e.g., macrophages, DCs), and stromal cells. NICIs function as neuroimmune synapse-like structures that permit real-time communication between vascular inflammation and central neural circuits (7).

In healthy vessels, NICIs contribute to homeostasis by regulating immune tone and facilitating vessel wall monitoring. Afferent nociceptive neurons detect inflammatory mediators (e.g., IL-1β, CCL2) and relay signals to the brainstem, particularly the nucleus tractus solitarius (NTS), thereby initiating autonomic feedback loops. Sympathetic efferents project back to the same vascular sites, releasing NE locally to modulate immune cell activation, antigen presentation, and cytokine production (7).

In addition to neurotransmitters, NICIs also house neuropeptides such as calcitonin gene-related peptide (CGRP), which has been shown to influence endothelial barrier function and shift macrophage phenotype (67, 68). In healthy arteries, functionally relevant NICIs are absent and arise de novo during disease onset, but their structural and functional plasticity makes them susceptible to extensive remodeling during pathological states such as atherosclerosis, hypertension, and autoimmune vasculitis. This potential for pathological rewiring underscores their importance as early sentinels of immune dysregulation.

Chronic psychosocial stress is increasingly recognized as a non-traditional but powerful accelerator of atherosclerosis through coordinated dysregulation of both the hypothalamic–pituitary–adrenal (HPA) axis and the autonomic nervous system. Activation of the HPA axis leads to elevated levels of CRH, which not only orchestrates systemic glucocorticoid responses but also exerts direct proinflammatory effects at the vascular level—promoting endothelial hyperpermeability and enhancing pro-inflammatory cytokine release from macrophages (69). Study has demonstrated that CRH directly promotes atherosclerosis progression by inducing endothelial inflammation. In LDLR^⁻/⁻ mice, exogenous CRH administration significantly exacerbated plaque development, accompanied by increased VCAM-1 expression and activation of the NF-κB signaling pathway, which together facilitate leukocyte recruitment. These pro-atherogenic effects were receptor-dependent and effectively suppressed by pharmacological inhibition of CRH receptor 1 (CRHR1). Importantly, this CRH–CRHR1 signaling pathway acts independently of systemic lipid metabolism, indicating a local vascular mechanism contributing to atherogenesis beyond classical metabolic factors (70).

Concomitantly, stress reduces parasympathetic tone, impairing the cholinergic anti-inflammatory reflex that is essential for limiting vascular inflammation. In this pathway, acetylcholine—originating from neuronal or potentially non-neuronal sources—binds to α7nAChRs on macrophages and endothelial cells, a receptor interaction supported by evidence from in vivo and in vitro studies demonstrating suppression of pro-inflammatory cytokine production (11, 55). However, this regulatory pathway is often compromised in chronic inflammatory states. In ApoE^⁻/⁻ mice, functional impairment of baroreflex control through sino-aortic denervation significantly exacerbates plaque burden, which is partially rescued by administration of selective α7nAChR agonists. This supports a critical role for vagal integrity in restraining local immune activation and endothelial dysfunction during atherogenesis (71).

Conversely, SNS overactivity enhances leukocyte recruitment and proinflammatory polarization via local NE release, primarily through β1-adrenergic receptor (β1-AR) and α-AR activation. Chronic SNS activation promotes myelopoiesis via β1-AR, increasing circulating inflammatory monocytes that infiltrate atherosclerotic plaques, effects reversed by non-selective β-adrenergic blockade (targeting both β1- and β2-AR) (72). NE also modulates neutrophil function and polarization, skewing them toward an immunosuppressive N2 phenotype while reducing their proinflammatory activity, although the precise implications of this polarization in atherosclerosis remain context-dependent (73).

Importantly, these autonomic imbalances do not occur in isolation but contribute to a pathophysiological feed−forward loop. CRH can directly enhance macrophage pro−inflammatory cytokine production, as shown by augmented TNF−α, IL−1β and IL−6 responses in LPS−stimulated macrophages (74). Meanwhile, catecholamines released from sympathetic nerve activation exhibit rhythmic, tissue-specific modulation of leukocyte adhesion to the vascular endothelium, promoting localized vascular inflammation with circadian variations (75). Notably, chronic inflammation is associated with increased sympathetic innervation density in the perivascular adventitia—suggesting neural remodeling reinforces immune activation (7). Collectively, these findings support a circuit in which autonomic imbalance, excessive sympathetic tone coupled with impaired parasympathetic anti-inflammatory signaling, facilitates vascular inflammation and plaque progression.

A growing body of experimental evidence supports the pivotal role of neuropeptides in orchestrating local immune responses in atherosclerosis. Among these, pituitary adenylate cyclase-activating polypeptide (PACAP), particularly its predominant isoform PACAP-38, has emerged as a key anti-inflammatory neuromodulator. In PACAP-deficient ApoE^⁻/⁻ mice (PACAP^⁻/⁻:ApoE^⁻/⁻), plaques exhibit significantly increased area, macrophage infiltration, and foam cell formation, accompanied by elevated TNF-α expression, indicating that endogenous PACAP constrains proinflammatory macrophage activation (76). Activation of its high-affinity receptor PAC1 using the selective agonist Maxadilan attenuates plaque burden by over 40%, reduces apoptotic cell accumulation, and suppresses IL-1β and TNF-α in LDLR^⁻/⁻ mice, without altering circulating lipids, suggesting local immunomodulatory effects (76). These findings underscore PACAP–PAC1 signaling as a vascular anti-inflammatory pathway with translational potential (77).

Beyond PACAP, other neuromodulators are increasingly recognized as crucial players in vascular immune regulation. Neuropeptide Y (NPY), highly expressed in sympathetic nerves, promotes vascular smooth muscle cell (VSMC) proliferation and M1 macrophage polarization (78). In a rat model of carotid balloon injury, slow-release NPY delivery induced occlusive atherosclerotic-like lesions containing lipid cores, macrophage infiltrates, thrombi, and neovessels, despite the absence of metabolic abnormalities or atherogenic diet. These effects were significantly attenuated by selective blockade of the Y1 receptor, with partial efficacy by Y5 receptor inhibition, implicating Y1R-mediated signaling as a key driver of NPY-induced vascular pathology (79).

Substance P (SP), via NK1 receptors, exerts dual effects depending on disease phase. In early atherogenesis, SP enhances monocyte recruitment and proinflammatory cytokine release, whereas in chronic stages it may promote tissue repair by stimulating Treg responses (80). Similarly, Secretoneurin is a pleiotropic peptide that promotes endothelial regeneration and angiogenesis but may also facilitate VSMC migration and contribute to fibrous cap destabilization (81).

Other modulators such as brain-derived neurotrophic factor (BDNF) and Galanin add further complexity. BDNF, traditionally known for its role in neuronal plasticity, is also expressed in human atherosclerotic plaques, particularly within smooth muscle cells, macrophages, and fibroblasts. Clinical imaging and immunohistochemistry studies have shown that elevated plasma BDNF levels correlate with increased macrophage infiltration in coronary plaques, suggesting a potential link to plaque vulnerability. Additionally, in vitro studies indicate that BDNF can enhance NAD(P)H oxidase activity in vascular cells, implicating a role in promoting oxidative stress within the vascular (82). Galanin is a neuropeptide that modulates autonomic tone and metabolic function and exhibits context-dependent immunoregulatory properties. In human monocytes and macrophages, galanin induces either pro-inflammatory (e.g., TNF-α, IL-1β, CXCL8) or anti-inflammatory (e.g., IL-10) cytokine expression depending on the activation state, demonstrating its bidirectional immune effects (83). Moreover, signaling through the GAL3 receptor has been shown to enhance the responsiveness of innate immune cells to inflammatory cues in specific inflammatory contexts, further supporting a potential pro-inflammatory role of galanin in chronic vascular inflammation (84).

Together, these findings suggest that atherosclerosis is modulated by a dynamic array of neuropeptides with context- and cell-specific effects. PACAP plays dominant anti-inflammatory roles, whereas NPY and SP may exacerbate inflammation depending on timing and receptor signaling. Understanding the spatial and temporal orchestration of these neuromodulators—and their interactions with neuroimmune interfaces such as NICIs, offers new opportunities for precision therapy.

Emerging evidence reveals that atherosclerotic inflammation induces profound structural and functional remodeling of the vascular adventitia, giving rise to specialized NICIs. In advanced lesions of both ApoE^⁻/⁻ mice and human coronary arteries, high-resolution imaging has demonstrated dense networks of sympathetic and sensory nerve fibers interwoven with clusters of macrophages, T and B lymphocytes, and smooth muscle cells in the adventitial layer, forming integrated hubs of bidirectional artery–brain communication (7, 75).

NICIs play dual and dynamic roles in coordinating neural and immune signals. First, afferent sensory fibers expressing TRPV1 and CGRP detect inflammatory cues and transmit them via dorsal root and nodose ganglia to autonomic centers in the brainstem, parabrachial nucleus, and hypothalamus (7). Second, efferent sympathetic pathways descend from these regions to the vascular adventitia through spinal and celiac ganglia, where they release NE, modulating leukocyte behavior and endothelial activation (75). Ablation of the celiac ganglion in aged atherosclerotic mice disrupted NICI integrity, attenuated local immune activation, and reduced plaque progression, indicating that this peripheral neural circuit contributes to disease progression at late stages (7).

Within NICIs, the TRPV1–CGRP axis functions as a key sensory immunomodulatory pathway. In the context of atherosclerosis, inflammatory cues such as LPS/TLR4 signaling, local acidosis, and endogenous lipid mediators, including capsaisin, anandamide (AEA) and N-arachidonoyl dopamine (NADA), sensitize TRPV1 channels expressed on perivascular sensory afferents (85–87). Upon activation, TRPV1 induces the release of CGRP, a vasodilatory neuropeptide that suppresses pro-inflammatory cytokine production, notably TNF-α in macrophages and IL-12 in dendritic cells (88, 89). Although specific suppression of CXCL2 has not been directly demonstrated, these findings collectively support a broader anti-inflammatory role for CGRP in myeloid cell regulation. Moreover, CGRP enhances endothelial nitric oxide synthase (eNOS) activity and inhibits NF-κB–dependent chemokine expression, such as CCL2 and CXCL8, thus limiting monocyte adhesion and transmigration (90). Additionally, CGRP restrains smooth muscle cell proliferation and reducing neointimal hyperplasia (91). Of note, prolonged TRPV1 activation may induce receptor desensitization through calcium-dependent dephosphorylation mechanisms, potentially weakening its neuroprotective output in chronic inflammation settings (92).

Crucially, NICIs structurally integrate with adventitial tertiary lymphoid organs (ATLOs), which arise in response to chronic vascular inflammation and whose development depends on de novo innervation from sympathetic and sensory fibers, as demonstrated in recent experimental models (7, 93). Such nerve ingrowth not only provides structural linkage but also enables bidirectional communication between vascular sensory/autonomic circuits and ATLO-resident immune cells, potentially shaping local antigen presentation, cytokine milieus, and lymphoid organization during atherogenesis. In aged ApoE^⁻/⁻ mice, ATLOs emerge as organized immune aggregates within the adventitia, comprising B-cell follicles, germinal centers, and high endothelial venules (93). study reported extensive nerve fiber sprouting within ATLOs, marked by GAP-43 and Synapsin, forming ultrastructural synapse-like contacts within nanometer proximity to CD45⁺ immune cells (7). These neuro-immune junctions function as dynamic interfaces for rapid sensing and modulation of immune activity within the vascular wall.

Collectively, NICIs and ATLOs convert the adventitia into a neuroimmune nexus—capable of integrating, amplifying, and transmitting vascular inflammatory signals through bidirectional neuroimmune communication. These findings shift the paradigm of atherosclerosis from a purely metabolic and inflammatory disease to one with defined neuroimmune architecture and functionality. An unresolved challenge is reconciling the anti-inflammatory and vasoprotective actions of CGRP with the potentially deleterious effects of de novo innervation and NICI/ATLO expansion during atherogenesis, whether these represent stage-dependent phenomena or context-specific signaling outcomes remains to be determined. Therapeutic targeting of specific NICI components, such as reinforcing CGRP-mediated vascular protection, restoring vagal α7nAChR signaling, or blocking maladaptive sympathetic outputs, may offer novel strategies for halting plaque progression and reducing cardiovascular events. Future studies should prioritize the temporal dynamics, cell-specific interactions, and plasticity of NICIs across disease stages to enable precision neuromodulation in atherosclerosis.

Preclinical studies support the efficacy of vagus nerve stimulation (VNS) as a targeted anti-inflammatory approach in atherosclerosis. While direct evidence in ApoE^⁻/⁻ mice is limited, pharmacological activation of α7nAChRs, a key mediator of vagal signaling, significantly reduces plaque burden, promotes M2 macrophage polarization, and lowers IL-1β and TNF-α levels (99).

A recent study of a novel small-molecule agonist, AZ6983, confirmed the central role of α7nAChR: in ApoE^⁻/⁻ mice AZ6983 reduced plaque burden by ~37–49 % versus control, dampened serum cytokines, and increased macrophage phagocytic capacity, recapitulating key functional endpoints attributed to VNS (100). Complementing these findings, imaging in human atherosclerotic vessels identified α7nAChR expression co-localized with macrophage-rich areas, lending translational significance to the mouse data (100).

Mechanistically, α7-mediated anti-inflammatory effects extend beyond cytokine suppression. A study demonstrated that macrophage recruitment into inflamed tissue depends on α7nAChR regulation of integrin αMβ2 expression; macrophages lacking α7 signal showed impaired migration in 3D matrices and in vivo endotoxemia models (101). These findings help explain how VNS and α7 agonism modulate plaque cellularity and stability by restricting monocyte/macrophage infiltration and favoring efferocytosis.

Despite therapeutic promise, VNS efficacy depends heavily on stimulation parameters. Low-frequency stimulation (1–10 Hz) primarily activates afferent fibers and suppresses sympathetic output, while higher frequencies (20–30 Hz) engage broader autonomic responses, including cardiac effects (102). Efforts to achieve fiber-selective targeting in VNS are challenged by significant anatomical variability and inconsistent electrode positioning in humans. The vagus nerve’s fascicular organization exhibits considerable interindividual differences, complicating reproducible and precise activation of desired fiber populations using cuff electrodes (103). Moreover, long-term clinical use of VNS can produce side effects such as bradycardia and hoarseness, which may impact patient compliance and quality of life (104); rare but serious cardiac adverse events like periodic bradycardia have also been reported, especially in pediatric cases (105). These technical and physiological limitations, combined with individual differences in disease stage and comorbidities, remain key barriers to the widespread clinical translation of fiber-selective VNS therapies.

α7nAChR agonists represent a pharmacologic route to harness the anti-inflammatory benefits of VNS without implantable devices. AZ6983 offers proof-of-concept: systemic administration in ApoE^⁻/⁻ mice reduced plaque burden, suppressed TNF-α, and enhanced macrophage phagocytosis via α7 engagement (100). Translational relevance is bolstered by evidence that α7nAChR is expressed in human atherosclerotic plaques, suggesting direct targeting of lesion macrophage populations may be feasible (106).

Beyond cytokine regulation, recent in vivo model of endotoxemia have demonstrated a distinct role for α7nAChR in regulating immune cell trafficking: α7nAChR deficiency markedly impairs macrophage recruitment to inflamed organs, including lungs and liver, by downregulating key integrins such as αMβ2, thereby limiting integrin-mediated migration (101). These findings underscore α7 agonists’ potential not only to suppress pro-inflammatory cytokine production but also to prevent immune cell accumulation in atherosclerotic plaques via modulation of integrin-dependent macrophage trafficking.

While these features suggest a degree of pathway specificity, their actual spatial precision in vivo remains an open question. For example, work by Simon et al. (11), indicates that in the splenic anti-inflammatory reflex, key α7nAChR-dependent steps may occur in upstream autonomic ganglia such as the celiac ganglion, rather than solely on plaque-resident macrophages. This raises the possibility that systemic α7 agonists might influence multiple anatomical sites along the reflex arc, not all of which are disease specific.

These pharmacologic strategies offer precision over systemic anti-inflammatories. Targeting α7nAChR allows pathway-specific modulation of immune responses, minimizing off-target immunosuppression (107). Moreover, allosteric modulators like PNU-120596 significantly enhance receptor responsiveness, enabling lower dosing and increased specificity in reducing inflammatory signaling (108).

However, concerns remain: α7 agonists must avoid desensitization of receptor function and do not yet have established long-term safety profiles in vascular patients (109). Another unresolved issue is tissue specificity, α7nAChR is expressed in multiple cell types (e.g. neurons, epithelial cells), raising potential for unintended effects unless cell-targeted delivery approaches are employed (110).

Efforts are ongoing to develop next-generation α7 modulators with biased signaling properties or restricted biodistribution. Combining pharmacologic agents with localized VNS or transcutaneous auricular VNS may synergize inflammatory suppression while reducing systemic exposure. Overall, precision α7 pharmacology offers a promising, device-independent alternative to neuromodulation, but its optimal targeting strategy in atherosclerosis will require further refinement and experimental validation.

Study highlights that beyond conventional lipid-lowering therapies, anti-cytokine agents also exert profound modulatory effects on neuroimmune circuits involved in atherosclerosis. The landmark CANTOS trial demonstrated that inhibiting IL-1β with canakinumab reduces major adverse cardiovascular events without altering lipid profiles, supporting the immunomodulatory relevance of IL-1β signaling in plaques (4). While CANTOS itself did not directly assess neural endpoints, more recent preclinical studies indicate that IL-1β can also modulate arterial nociceptive sensory fibers and neuroimmune signaling (6), thereby providing a mechanistic link between cytokine blockade and potential effects on vascular innervation. Genetic deletion of IL-1β in ApoE⁻/⁻ mice leads to a significant reduction in plaque burden, accompanied by decreased monocyte adhesion and inflammatory cytokine expression (111). Intriguingly, IL-1β has been shown to sensitize TRPV1⁺ sensory neurons in inflammatory skin and joint diseases, promoting neuropeptide release and local immune amplification (112). Given the established role of TRPV1–CGRP signaling within NICIs in atherosclerosis, it is plausible that IL-1β blockade might also dampen neurogenic inflammation in vascular lesions. While direct evidence for IL-1β–TRPV1 crosstalk in atherosclerosis is lacking, future investigations could reveal whether sensory neuroimmune desensitization contributes to the plaque-stabilizing effects of anti-cytokine therapy.

IL-6 receptor antagonism, using agents like tocilizumab, may provide benefits that extend beyond standard anti-inflammatory effects. Although direct evidence in ApoE^⁻/⁻ mice linking IL-6R blockade to modulation of plaque-associated sympathetic fibers remains unavailable, preclinical research indicates that IL-6 signaling robustly influences sympathetic nervous system activity. For example, intracerebroventricular IL-6 administration in rats was found to significantly increase splenic sympathetic nerve discharge and elevate circulating norepinephrine levels, highlighting a central IL-6–driven sympathetoneural axis (113). Additionally, systemic IL-6 elevation is commonly associated with increased sympathetic tone in chronic inflammatory conditions, providing a mechanistic link to neuroimmune modulation in vascular disease (113, 114). These findings support a plausible dual mechanism: IL-6R blockade could suppress inflammatory signaling and indirectly attenuate sympathetic-driven neuroimmune activation in atherosclerosis. However, targeted in vivo studies are needed to confirm whether IL-6R-targeted therapies modulate sympathetic innervation or β₂-adrenoceptor expression in plaque-associated nerves.

These immunomodulators differ from traditional neuromodulatory therapies. Whereas VNS and pharmacologic agonists directly target neural circuits, cytokine inhibitors reprogram neuroimmune interactions indirectly, quieting both inflammatory triggers and sensitized neural feedback loops. While no studies have directly examined the combined effects of VNS and canakinumab in LDLR^⁻/⁻ mice, their complementary mechanisms of neural circuit modulation and cytokine inhibition suggest the potential for synergistic benefits in reducing plaque size and systemic inflammation. Future experimental work is needed to evaluate this possibility.

However, targeting cytokines is not without challenges. Systemic neutralization of IL-1β or IL-6 carries infection risk, as these mediators are essential for host defense. For instance, the CANTOS trial reported significantly elevated rates of serious infections and sepsis among individuals receiving canakinumab compared to placebo (4). Moreover, IL-1β antagonists can blunt fever-induced vagal reflexes, potentially shifting autonomic balance—animal studies show that subdiaphragmatic vagotomy blocks IL-1β–induced fever and behavioral changes, underscoring the role of vagal afferents in mediating inflammatory responses (115). Emerging clinical data also link sustained IL-6 suppression to transient vagal hypoactivity: heart rate variability (HRV), a key measure of parasympathetic function, inversely correlates with inflammatory markers such as IL-6 and CRP in patients with rheumatoid arthritis (116). These observations underscore the need for therapies that selectively modulate pathogenic neuroimmune pathways while preserving beneficial autonomic reflexes.

In summary, anti-cytokine agents have proven efficacy in cardiovascular trials and show emerging neuromodulatory effects by quelling both inflammatory and neural feedback. However, their non-specific nature raises safety concerns. Combinatorial approaches with electrical or pharmacologic neuromodulation may achieve greater precision and reduced side effects, which sheds light on a balanced “neuro-cytokine” therapeutic axis for atherosclerosis.

The evolving understanding of plaque-centric neuroimmune systems, NICIs, creates fertile ground for novel therapies that directly target nerve–immune interfaces within the adventitia. For instance, Sensory TRPV1 signaling has been implicated in modulating vascular–sympathetic reflexes and homeostatic blood pressure regulation, suggesting that TRPV1 antagonists may offer a way to interrupt stress-induced pro-inflammatory circuits—though direct evidence in atherosclerotic plaque models remains pending (117). Separately, centrally administered gabapentin modulates blood pressure and heart rate via the NTS in hypertensive rats through NOS-dependent mechanisms, indicating its capacity to recalibrate autonomic reflexes—though synergy with α7nAChR agonists in AS has yet to be explored (118).

Within peptide neuromodulators, PACAP and CGRP have emerged as promising yet divergent targets. As mentioned, PACAP–PAC1 activation via Maxadilan inhibits macrophage TNF-α production and increases regulatory IL-10 expression in murine plaques independent of lipids (76). Conversely, CGRP antagonism, widely used in migraine, presents a cautionary tale: galcanezumab-treated ApoE^⁻/⁻ mice exhibit increased plaque macrophage infiltration and vessel wall inflammation, highlighting CGRP’s protective role in vascular homeostasis (119). These findings have major translational implications—identifying CGRP inhibitors as potentially contraindicated in high-risk cardiovascular patients, while spotlighting PACAP agonists as therapeutic candidates.

Challenges loom in targeting NICIs and peptidergic systems. Anatomical heterogeneity across arterial beds may limit drug access, and long-term manipulation of sensory fibers may disrupt homeostatic neurovascular reflexes, as sensory innervation density and function vary widely by vascular territory (120). Moreover, biased agonism at PAC1 receptors may differentially modulate vascular versus neural signaling, with PAC1-mediated vascular relaxation and central neural sensitization showing distinct pharmacology—necessitating careful pharmacodynamic profiling (121).

However, the emerging clinical use of CGRP blockade in migraine and the translational potential of PAC1 agonists such as Maxadilan underscore the urgent need to evaluate cardiovascular safety and long-term immunomodulatory outcomes in relevant patient populations. Future studies should systematically map neuropeptide expression dynamics and receptor distribution across atherosclerosis stages to inform the rational design of targeted interventions.

Nevertheless, integrating structural NICI mapping with focused neuromodulation holds promise. Combined approaches, e.g., nanoparticle-mediated PACAP delivery to adventitial nerve sheaths, or localized TRPV1 blockade using targeted antibodies, could allow lesion-specific intervention, although agonist such as capsaicin should be avoided due to its side effects (122, 123). These strategies may showcase integrated mechanistic insight and therapeutic innovation. Overall, therapy aimed at disrupting pathological nerve–immune crosstalk, via PACAP agonists, CGRP modulators, and NICI-directed interventions, offers a new frontier in precision atherosclerosis management.

Several translational barriers complicate the therapeutic potential of targeting neuroimmune pathways in AS application in human disease. One major obstacle lies in the anatomical and functional complexity of autonomic circuits. VNS, while potently anti-inflammatory in ApoE^⁻/⁻ mouse models via activation of α7nAChR, expressing macrophages, often results in non-specific activation of adjacent neural branches when translated into larger animals or humans, due to the anatomical complexity and lack of fiber-type selectivity with conventional cuff electrodes (124). Standard cuff electrodes lack fiber-specific resolution, inadvertently activating laryngeal, leading to coughing or bradycardia (124, 125). Even in recent animal studies (adult male Sprague-Dawley rats and Merino ewes) employing closed-loop or optogenetic approaches, achieving selectivity for anti-inflammatory vagal efferents remains technically demanding and largely untested in AS-specific contexts (126).

Beyond technical hurdles, the systemic effects of neuromodulatory peptides, such as CGRP and PACAP, raise concerns about long-term safety and vascular specificity. CGRP receptor antagonists (e.g., erenumab) are now widely used for migraine prophylaxis, and large-scale post-marketing data suggest they do not increase major adverse cardiovascular events (127). However, these findings are based on low-risk populations and may not fully translate to individuals with established atherosclerosis, where CGRP plays a vasoprotective and anti-inflammatory role. Indeed, ApoE/CGRP double-knockout mice develop significantly larger plaques and enhanced macrophage activation, underscoring α-CGRP’s protective role in atherogenesis (119). Conversely, PACAP-based therapies remain at the preclinical stage: the PAC1 receptor agonist Maxadilan markedly reduced plaque incidence (from ~75 % to ~28 %) and lumen stenosis in ApoE ^−/− mice, lowered TNF-α⁺ and IL-1β⁺ areas, and decreased apoptosis in lesions—even under cholesterol-enriched diets (76). However, these effects are confined to murine models; no safety or efficacy data exist in non-rodent species, and translation to humans remains speculative.

Another challenge is the striking inter-individual variability in autonomic tone, inflammatory responses, and neural-immune coupling across patients. Factors such as age, metabolic syndrome, autonomic neuropathy, and even sleep quality alter neuroimmune balance, potentially modulating response to interventions. For instance, HRV, widely used as a proxy for vagal tone, is inversely associated with circulating markers of inflammation in cardiovascular disease cohorts: lower HRV correlates with elevated IL-6, CRP, and fibrinogen levels (128–130). Additionally, in a large young adult cohort (N = 2,064), reduced HRV was independently associated with higher monocyte and leukocyte counts, further suggesting HRV as a physiological biomarker of immune activation (131). These findings underscore the need for physiological stratification using HRV or related autonomic markers to identify individuals most likely to benefit from neuromodulatory therapies.

Adding further complexity, recent evidence indicates that VNS does not always act through the canonical α7nAChR pathway. In inflammatory disease models of acute lung injury, VNS-induced immunosuppression was abolished by adrenalectomy, but not by α7nAChR blockade, suggesting a vagus–adrenal–catecholamine axis rather than direct cholinergic signaling (132, 133). This distinction is crucial for AS, where peripheral nerve terminals may act via local versus systemic pathways, making target engagement and mechanistic verification essential in future trials.

Finally, chronic neuromodulation may induce neural plasticity or receptor desensitization, as seen in prolonged CGRP or PACAP exposure, potentially diminishing efficacy over time (134). Despite their promising immunomodulatory profiles, long-term studies evaluating tolerance, feedback inhibition, or compensatory sympathetic activation are largely absent in current AS models. Moreover, while bioelectronic and pharmacologic therapies hold distinct promise, their combined effects, whether synergistic or antagonistic, remain unexplored, raising critical questions for therapeutic design.

In conclusion, advancing neuroimmune-targeted therapies for atherosclerosis will require refined neuromodulation tools with enhanced circuit selectivity, rigorous safety validation of peptidergic drugs, and patient stratification approaches grounded in real-time autonomic and inflammatory biomarkers. Addressing these challenges through integrated engineering, pharmacological, and immunological frameworks is essential to realize the clinical potential of this emerging field.