Macrophages, as central phagocytes of the innate immune system, play a central role in the pathogenesis of AAD by mediating inflammation and presenting antigens to initiate adaptive responses (6). They are broadly classified into pro-inflammatory M1 and anti-inflammatory M2 subsets. In AAD lesions, M1 macrophages predominate, driven by STAT and NF-κB signaling cascades regulated by miR-720 and miR-127. This polarization promotes the release of TNF-α, ROS, IL-1, IL-6, and NO, while suppressing IL-12, IL-23, and IL-10, thereby amplifying vascular injury (24, 25). During early AAD stages, M1 macrophages infiltrate from the adventitia into the media, initiating extracellular matrix degradation (6), whereas M2 macrophages emerge later to support repair. Macrophage-derived MMPs and interleukins sustain inflammatory loops via cytokine signaling (26). Moreover, angiotensin II exacerbates macrophage recruitment and activation through the KLF6–GM-CSF axis, upregulating MMPs and ADAMTS-1 expression, which collectively compromise aortic wall integrity (27).

Neutrophils initiate acute inflammation by rapidly infiltrating injured sites and orchestrating secondary immune recruitment via cytokine release, thus forming the frontline defense barrier (28). In AAD, activated neutrophils contribute to both inflammatory injury and maladaptive tissue remodeling (4). Neutrophil extracellular traps (NETs) are formed through a process known as NETosis, which is triggered by the generation of reactive oxygen species (ROS), calcium influx, and activation of peptidylarginine deiminase 4 (PAD4), leading to chromatin decondensation and histone citrullination (29–31). NET-derived components such as neutrophil elastase (NE), myeloperoxidase (MPO), and citrullinated histones exert cytotoxic effects on vascular smooth muscle cells (VSMCs) by disrupting cell membrane integrity, promoting apoptosis, and inducing phenotypic switching toward a synthetic, matrix-degrading phenotype (32–34). In macrophages, these NET components enhance inflammasome activation, upregulate pro-inflammatory cytokines, and perpetuate the inflammatory cycle within the aortic wall (35, 36). NET accumulation in AAD correlates with disease severity, promotes macrophage cytokine secretion, and facilitates Th17 polarization (4, 37). NET-associated components, such as NE and its target TBL1x, facilitate inflammatory cell migration and vascular smooth muscle cell phenotypic switching (5). Clinical studies reveal elevated granzyme and NET markers in aortic tissues of AAD patients, with circulating NET levels linked to in-hospital mortality and one-year survival (4). In experimental models, neutrophil depletion or inhibition of vascular infiltration reduces MMP expression and significantly decreases AAD incidence (38), underscoring neutrophils and NETs as potential therapeutic targets ( Figure 1 ).

T lymphocyte activation plays a critical role in the pathogenesis of AAD. Elevated levels of CD3⁺, CD4⁺, CD8⁺, and CD45⁺ T cells have been identified in the aortic wall of AAD patients, indicating active local immune involvement (39). Within T helper subsets, Th1, Th9, Th17, and Th22 cells and their transcriptional regulators are obviously upregulated, while Th2 and Tregs are downregulated, suggesting a protective role for the latter (40). Th17 and Tregs originate from a shared precursor and are both dependent on TGF-β; however, IL-6 promotes Th17 differentiation at the expense of Tregs (41). Elevated IL-6 and Th17-derived IL-17 levels have been confirmed in AAD tissues (42), supporting the therapeutic potential of IL-6 inhibition. IL-17 promotes extracellular matrix (ECM) degradation by stimulating MMP-2 and MMP-9 expression in VSMCs and macrophages (42–45), weakening the structural integrity of the aortic wall by degrading elastin and collagen (46, 47). Besides, IL-17 stimulates the secretion of pro-inflammatory cytokines and chemokines (IL-1β, TNF-α, CCL2), further enhancing immune cell recruitment and inflammation within the aortic media (48–50). The IL-6/STAT3 axis acts as a key amplifier in this cascade. IL-6 binding to gp130 activates JAKs, driving STAT3 phosphorylation and nuclear localization, thereby enhancing transcription of RORγt, the master regulator of Th17 lineage commitment and IL-17 production (51–54). STAT3 activation also promotes MMP expression in vascular cells, intensifying ECM degradation. This feedforward loop—linking IL-6, STAT3, and IL-17—potentiates vascular inflammation, smooth muscle cell phenotypic switching, and structural disintegration, hallmarks of AAD (55). Tregs, though typically anti-inflammatory via IL-10 production, also exhibit functional heterogeneity; increased CD25⁺ Tregs have been linked to vascular inflammation in carotid artery disease (56, 57). Additionally, Fas–FasL-mediated apoptosis of memory T cells may induce smooth muscle cell loss and vascular wall weakening, exacerbating AAD risk (58).

Monocytes, circulating components of the adaptive immune system, possess phagocytic capacity and activate other immune cells. Based on surface markers, they are classified into three subsets: classical (CD14⁺⁺CD16⁻), intermediate (CD14⁺⁺CD16⁺), and non-classical (CD14⁺CD16⁺) (59). Among these, classical monocytes exhibit the highest pro-inflammatory potential, characterized by robust phagocytic activity and the capacity to secrete cytokines such as TNF-α and IL-1β upon activation (60). These cells are rapidly recruited to sites of vascular injury and are primarily responsible for initiating and amplifying inflammatory responses in the early phase of AAD (61, 62). In AAD, classical monocytes are markedly elevated, while intermediate subsets are reduced. Activated monocytes interact with platelet glycoprotein Ibα (GPIbα) and coagulation factor XI (FXI) to promote local thrombin generation, thereby exacerbating vascular inflammation and hypertension, and accelerating AAD progression (63). Haider et al. (64) demonstrated that IL-14 stimulation reduces NF-κB p65 phosphorylation and decreases monocyte apoptosis in vitro, suggesting that beyond promoting macrophage differentiation, the NF-κB pathway may also support monocyte survival and differentiation. Monocytes also release low-density lipoprotein receptor-related protein 8 (LRP8), which triggers vascular inflammation and endothelial dysfunction, further implicating them in the pathogenesis of AAD (65). These findings imply that monocytes may also play a contributory role in Ang II–mediated AAD development.

The interleukin-6 (IL-6) cytokine family includes IL-6, IL-11, IL-30, IL-31, and non-IL molecules, primarily secreted by lymphocytes, monocytes/macrophages, adipocytes, tumor cells, and endothelial cells (66). Elevated IL-6 levels are observed in patients with AAD compared to healthy controls (67). Sano and Anzai (68) found that chemokine-dependent signaling induces neutrophilia and infiltration into the dissected aorta, where IL-6 contributes to aortic dilation and rupture. Tieu et al. (69) noted IL-6’s localization in the adventitia, promoting monocyte recruitment, MCP-1 secretion, vascular inflammation, and ECM degradation. The IL-6 signaling pathway involves gp130, which recruits co-receptors like the leukemia inhibitory factor (LIF) receptor and oncostatin M (OSM) receptor, activating JAK/STAT and MAPK cascades (70). These pathways enhance angiotensin II (Ang II) signaling, causing vasoconstriction via the renin-angiotensin system (RAS), elevating blood pressure and exacerbating aortic wall injury, leading to intimal tearing and false lumen formation (71). Chemokines are small proteins that guide the directional migration of cells through interactions with G protein–coupled receptors on target cells. Based on N-terminal cysteine residue arrangement, they are classified into five subfamilies: CXC, CX, CC, XC, and CX3C (72). Most studies focus on the inflammatory roles of the CXC and CC families. The CC family includes ~28 members, such as CCL2 (MCP-1), which enhances IL-6 expression and reduces macrophage apoptosis in aortic walls, mitigating Ang II–induced AAD progression (69). CCL3 (MIP-1β) has been linked to AAD, with elevated levels found in AAD patients (73). The CXC family includes ~17 members, such as CXCL1, which is upregulated in AAD and promotes neutrophil infiltration and IL-6 expression, leading to aortic dilation and rupture (74). CXCL4 exacerbates atherosclerosis by enhancing TLR2 signaling and lipid deposition at the aortic root. These findings highlight chemokines as critical mediators in vascular inflammation, warranting further research into their roles.

The tumor necrosis factor (TNF) superfamily includes over 20 members, such as TNF-α, B cell activating factor (BAF), photosensitizer-β (PS-β), TNF-related apoptosis-inducing ligand (TRAIL), and receptor activator of nuclear factor kappa-B ligand (RANKL), all of which potentiate inflammation through NF-κB signaling. Liu et al. (75) reported significantly increased serum TNF-α levels in AAD patients. TNF-α is also implicated in the regulation of vascular SMC apoptosis, a process central to AAD progression (76). Notably, the concentration of TNFα varies with disease stage and progression (77), suggesting temporal heterogeneity in its regulatory mechanisms and indicating the need for time-resolved studies. Interferons (IFNs), a class of cytokines with potent antiviral, antiproliferative, and immunomodulatory properties, are crucial components of innate immunity (78). IFNs are classified into type I, II, and III. Type I IFNs include IFNα, IFNβ, IFNδ, IFNϵ, and IFNκ, which exert broad antiviral and antiproliferative functions (79). Type II IFN (IFN-γ) is produced by T lymphocytes, antigen-presenting cells, and NK cells, and exerts immunoregulatory functions (80). Type III IFNs include IFN-λ1 (IL-29), IFN-λ2 (IL-28A), IFN-λ3 (IL-28B), and IFN-λ4. Among these, IFN-γ plays a central role in AAD progression. It stimulates macrophages to secrete IL-12 and IL-18, which further activate the NF-κB pathway, establishing a positive feedback loop that enhances IFN-γ expression (81). It also modifies the extracellular matrix (ECM) by enhancing neutrophil infiltration and stimulating MMP9 release. In aortic SMCs, IFNγ activates JNK signaling, leading to cJun phosphorylation and MMP2 upregulation (82). Furthermore, IFNγ contributes to SMC phenotypic switching, as evidenced by its ability to suppress contractile markers such as SM22α and calmodulin (83). Collectively, these findings support IFN-γ’s role in exacerbating vascular inflammation by modulating ECM remodeling and SMC plasticity.