Mediators Inflamm. 2026;2026(1):e1377824. doi: 10.1155/mi/1377824.
ABSTRACT
BACKGROUND: Psoriasis (PSO) and atherosclerosis (AS) are chronic inflammatory diseases that frequently coexist, with each condition exacerbating the other. However, the underlying mechanisms remain poorly understood, partly due to the lack of a suitable animal model that recapitulates this bidirectional comorbidity.
METHODS: PSO-AS mouse models were constructed by combining high-fat diet (HFD)-induced AS with imiquimod (IMQ)-triggered psoriatic inflammation in ApoE-/- mice. PSO severity was assessed via skin manifestation, hematoxylin and eosin (H&E) staining, PSO area and severity index (PASI) score, quantitative real-time PCR (qRT-PCR), and serum ELISA, while AS was assessed by en face Oil red O (ORO) staining of aorta, H&E staining, ORO staining, Sirius Red (SR) staining, and immunofluorescence (IF) staining of the aortic root section. Mechanistic insights were obtained via proteomics, machine learning (ML), and validation of macrophage polarization in both skin and plaques.
RESULTS: Chronic PSO model more closely resembles real-world conditions than acute PSO model. Combining the IMQ application with a HFD, both the PSO-AS group and the PSO group developed obvious psoriatic skin lesion, but the PSO-AS group showed the highest epidermal thickness, PASI scores, and expression levels of psoriatic biomarkers (Interleukin-17A [IL-17A] and Interleukin-23 [IL-23]) and inflammatory factors (e.g., tumor necrosis factor alpha [TNF-α] and Interleukin-6 [IL-6]), implying that AS may exacerbate PSO. Similarly, the PSO-AS and AS groups both developed obvious plaque in the aorta, while the PSO-AS group has the largest plaque area, necrotic core (NC) area, lipid content with the least fibrous cap (FC) thickness, and collagen content, illustrating that PSO conspicuously aggravated AS progression and led to an unstable plaque shift. Statistical analysis also confirms that PSO and AS mutually exacerbate each other, forming a vicious cycle that may be strongly associated with IL-17. Proteomics and ML revealed marked M1 macrophage polarization in PSO-AS mice. Validation by Western blot and IF showed upregulated M1 markers (CD86) and downregulated M2 markers (CD163) in both skin lesions and aortic roots, indicating that M1-skewed macrophages fuel the vicious cycle. Besides, we explore that IFIT3 may serve as a promising biomarker for M1 macrophages in PSO-AS skin.
CONCLUSIONS: This novel PSO-AS mouse model faithfully recapitulates the bidirectional exacerbation seen clinically and uncovers M1 macrophage polarization as a key driver of this comorbidity. The model provides a robust platform for mechanistic and therapeutic studies of PSO-associated cardiovascular disease (CVD).
PMID:42504112 | DOI:10.1155/mi/1377824