Loss of IGFBP-6 promotes monocyte-driven atherogenesis in periodontal disease

Periodontitis has been associated with an increased risk of atherosclerosis, potentially through altered systemic monocyte and macrophage function. We aimed to identify a differentially expressed protein in naïve monocytes from individuals with periodontitis compared to controls and investigate its association with pro-atherosclerotic monocyte and macrophage functions. Peripheral blood monocytes were isolated from individuals with periodontitis and matched controls. Proteomic analysis and bioinformatics identified insulin-like growth factor-binding protein-6 (IGFBP-6) as a protein of interest. IGFBP-6 protein was quantified in monocytes, macrophages, foam cells, and plasma using Western blotting. To model periodontitis in vitro, monocytes and macrophages were treated with Porphyromonas gingivalis lipopolysaccharide. Extracellular vesicles were analysed for IGFBP-6 content and activity. Foam cell formation, cholesterol transporter expression, monocyte adhesion, macrophage transmigration, inflammatory cytokine production, and apoptosis were quantified. IGFBP-6 levels were reduced intracellularly but elevated in plasma in periodontitis, and similar patterns were observed in lipopolysaccharide-treated cells. IGFBP-6 in extracellular vesicles lacked biological activity. Reduced IGFBP-6 protein was associated with increased foam cell formation and downregulation of ATP-binding cassette subfamily-G1 (ABCG1), independent of IGF signalling. Restoration of IGFBP-6 was associated with foam cell formation, inflammation and inhibited macrophage transmigration. These findings suggest that altered IGFBP-6 levels may contribute to the progression of atherosclerosis in periodontitis.