Hyperuricemia activates the TLR2–MAPK signaling axis in vascular macrophages to drive aortic dissection
B Zheng, B Li, B Zhang, S Sau, M Gao, L Zhang, Y Qiang, Z Liu, J Holm, K Zeng, Y Chang, Y YangAbstract
Background
Epidemiological and clinical evidence has consistently linked hyperuricemia to an increased risk of aortic dissection (AD), yet the molecular mechanism by which elevated uric acid (UA) activates macrophage-mediated aortic destruction remains unclear. Toll-like receptor 2 (TLR2) is a pivotal pattern-recognition receptor of innate immunity and vascular inflammation, making it a plausible direct link between UA and AD pathogenesis. Here, we hypothesized that TLR2 acts as the primary molecular sensor for UA, activating the downstream MAPK signaling cascade to drive sustained aortic wall inflammation and structural degradation, culminating in aortic dissection.
Purpose
This study aimed to investigate the molecular mechanism of UA triggering AD by activating the Toll-like receptor 2 (TLR2) and a series of subsequent molecular reaction, and to identify a novel therapeutic target.
Methods
A multi-level translational approach was utilized. In vitro, THP-1-derived macrophages were stimulated with gradient UA concentrations (0–10 mM). Causality was assessed using a TLR2-specific inhibitor (CU-CPT22) and specific MAPK inhibitors. In vivo, a spontaneous AD murine model was established via β-aminopropionitrile (BAPN) administration combined with a high-purine diet. Primary endpoints included TLR2 expression, MAPK phosphorylation (P38/JNK), pro-inflammatory cytokine secretion (IL-6, TNF-α, IL1β), and overall AD incidence. Specimens of dissected aortic tissue were evaluated via by using routine pathological examination and CD68+/TLR2+ double-immunofluorescence.
Results
In vitro, UA dose-dependently upregulated macrophage TLR2 mRNA and protein expression, provoking a robust pro-inflammatory cytokine response. Mechanistically, TLR2 inhibition significantly suppressed UA-induced P38 and JNK phosphorylation (>70% reduction, P < 0.01) and blunted cytokine secretion—an effect mirrored by Rosuvastatin, which similarly suppressed the P38/JNK signaling axis in THP-1 cells. In vivo, high-purine-fed BAPN mice exhibited significantly elevated serum UA levels and a drastically higher AD incidence compared to controls (72.5% vs. 12.5%, P < 0.01). Histopathology of dissected aortic wall revealed extensive elastic fiber fragmentation and dense CD68+ macrophage infiltration, with localized TLR2 upregulation. This phenotype was successfully restored by pharmacological TLR2 inhibition, which also attenuated structural degradation and reduced the incidence of AD to 25% (P < 0.01).
Conclusions
These findings unveil a critical role of the UA-TLR2-MAPK signaling axis as a critical driver of macrophage-mediated aortic inflammation. This study provides a novel mechanistic explanation for the clinical association between hyperuricemia and AD, suggesting that targeting the TLR2 pathway or aggressive uric acid management may offer potent preventive strategies for high-risk populations.UA-TLR2-MAPKFor image description, please refer to the figure legend and surrounding text.UA upregulates TLR2 expression in THP-1.For image description, please refer to the figure legend and surrounding text.