Fusobacterium nucleatum Accelerates Atherosclerosis via Macrophage-Driven Aberrant Proinflammatory Response and Lipid Metabolism

Abstract

Periodontitis, an oral chronic inflammatory disease, is reported to show an association with atherosclerotic vascular disease. <i>Fusobacterium nucleatum</i> is an oral commensal bacterium that is abundantly implicated in various forms of periodontal diseases; however, its role in the pathogenesis of atherosclerosis is unclear. This study aimed to elucidate the underlying pathogenic mechanisms of atherosclerosis induced by <i>F. nucleatum</i> to provide new insight on the prevention and treatment of atherosclerosis. We used an animal model, that is, ApoE^-/- mice were infected with <i>F. nucleatum</i> by oral gavage, and <i>in vitro</i> co-culture models to assess the pathogenicity of <i>F. nucleatum.</i> The results indicate that <i>F. nucleatum</i> ATCC 25586 invaded aortic tissues and substantially increased the progression of atherosclerotic lesions. In addition, <i>F. nucleatum</i> changed plaque composition into a less-stable phenotype, characterized with increased subcutaneous macrophage infiltration, M1 polarization, lipid deposition, cell apoptosis, and reduced extracellular matrix and collagen content. The serum levels of pro-atherosclerotic factors, such as interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein-1 (MCP-1), c-reactive protein, and oxidized low-density lipoprotein (ox-LDL) and microRNAs (miR-146a, miR-155, and miR-23b) were considerably increased after <i>F. nucleatum</i> stimulation, whereas HDL-c level was reduced. <i>F. nucleatum</i> induced <i>in vitro</i> macrophage apoptosis in a time- and dose-dependent manner. <i>F. nucleatum</i> facilitated ox-LDL-induced cholesterol phagocytosis and accumulation by regulating the expression of lipid metabolism-related genes (AR-A1, ACAT1, ABCA1, and ABCG1). <i>F. nucleatum</i> further worsened the atherosclerotic plaque microenvironment by considerably increasing the levels of IL-6; IL-1β; TNF-α; MCP-1; and MMP-2, 8, and 9 and by suppressing fibronectin (FN) 1 levels during foam cell formation. This study shows that <i>F. nucleatum</i> ATCC 25586 is implicated in atherosclerosis by causing aberrant activation and lipid metabolism in macrophage.