Adipose Tissue Macrophage-Derived Proplatelet Basic Protein Exacerbates Psoriasis-Associated Atherosclerosis by Inducing Mitochondrial Dysfunction in Aortic Endothelial Cells.

Abstract

Chronic inflammatory skin diseases, such as psoriasis, are increasingly recognized as systemic diseases associated with an elevated risk of cardiovascular disease. However, the molecular mechanisms underlying this comorbidity remain poorly defined. In this study, transcriptomic analysis of dermal adipose tissue from patients with psoriasis identified proplatelet basic protein (PPBP) as a significantly upregulated chemokine, with elevated expression observed both locally within adipose macrophages and systemically in the circulation. Functionally, Ppbpmice exhibited markedly attenuated psoriasiform skin inflammation, whereas administration of recombinant PPBP or topical imiquimod exacerbated atherosclerotic plaque formation in ApoEmice. Importantly, PpbpApoEmice developed significantly smaller atheromatous plaques than ApoEcontrols. Mechanistically, PPBP suppressed the expression of the zinc homeostasis regulator ZNG1F, leading to disrupted intracellular zinc balance, mitochondrial dysfunction, and oxidative stress in human coronary artery endothelial cells. Therapeutically, PPBP neutralization or treatment with the mitochondrial-targeted antioxidant Mito-TEMPO significantly mitigated imiquimod-exacerbated atherosclerosis in ApoEmice. To our knowledge, we identify a previously unrecognized PPBP-ZNG1F-mitochondria axis as a potentially critical immune-metabolic link between psoriasis and cardiovascular disease, highlighting PPBP as a promising biomarker and therapeutic target for reducing cardiovascular risk in chronic inflammatory skin diseases.