Single-cell transcriptomic landscape of psoriasis-accelerated atherosclerosis reveals immune remodeling and macrophage dysfunction
F Tan, R Wang, Y Jiang, Y Xia, Z Hu, J Tao, W YangAbstract
Background
Psoriasis, a chronic inflammatory skin disease, confers a significantly increased risk of atherosclerosis and cardiovascular events. However, the cellular and molecular mechanisms underlying this accelerated atherosclerosis remain poorly understood at single-cell resolution.
Methods
We performed single-cell RNA sequencing (scRNA-seq) on aortic plaques from a psoriasis-accelerated atherosclerosis (PSO-AS) mouse model compared to standard atherosclerosis (AS) controls. Cellular composition, transcriptional profiles, and pathway alterations were analyzed using bioinformatic approaches including dimensionality reduction, cluster identification, and gene set enrichment analysis (GSEA).
Results
ScRNA-seq revealed profound cellular remodeling in PSO-AS plaques, characterized by marked expansion of total macrophages, significant reduction in smooth muscle cells, and increased T cell infiltration compared to AS controls. Detailed macrophage subcluster analysis identified distinct functional shifts: pro-inflammatory Macro_Il1b (amplifying IL-1β-driven inflammation), lipid-metabolism-dysregulated Macro_Lipg (promoting HDL hydrolysis and generating pro-inflammatory lipids), and adhesion-related Macro_Itgad (facilitating retention within plaques) were substantially enriched in PSO-AS plaques. Conversely, the protective Macro_Trem2 subset, responsible for efferocytosis and lipid clearance, was sharply decreased, indicating impaired resolution capacity. T cell compartment analysis revealed an increase in CD8⁺ Tpex (precursor exhausted) cells reflecting sustained antigen stimulation; expansion of CD4⁺ Tfh cells suggesting enhanced B-cell help and humoral immunity; and reductions in γδ T cells and CD4⁺ naïve T cells consistent with chronic immune activation and redistribution. GSEA confirmed upregulation of inflammatory, lipid metabolic, and leukocyte adhesion pathways in PSO-AS plaques, while phagocytosis and TREM2 signaling were significantly downregulated.
Conclusion
Psoriasis accelerates atherosclerosis by inducing profound immune remodeling at single-cell resolution, characterized by expansion of pro-inflammatory macrophage subsets, loss of protective Trem2⁺ macrophages, and adaptive immune activation. These changes create a plaque microenvironment prone to necrotic core expansion, impaired efferocytosis, and heightened vulnerability, providing new mechanistic insights into psoriasis-associated cardiovascular disease.