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TNF-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine belonging to the TNF superfamily and regulates apoptosis, inflammation, cell proliferation and angiogenesis. TWEAK, along with its receptor Fn14, have been detected in atherosclerotic lesions, particularly in regions rich in macrophages and foam cells. We investigated the role of TWEAK/Fn14 interactions in atherosclerotic plaque development in a mouse model of atherosclerosis. ApoE-/- mice were injected twice a week for 12 weeks with 100μg of a TWEAK-inhibiting protein, Fn14:Fc. Treatment began at either 5 weeks of age (early treatment) or 17 weeks of age (delayed treatment). Control mice received isotype-matched antibody. Aortic arches including the main branch points were analyzed for plaque size and phenotype. There were no differences in total plaque area between Fn14:Fc-treated and control mice in either of the early or delayed treatment groups. There were significantly smaller advanced plaques in Fn14:Fc-treated mice in the early treatment group (Fn14:Fc 30222±5833 μm2 vs. control 80960±14963 μm2, p<0.05). In the delayed treatment group, significantly more initial plaques compared to advanced plaques were observed in Fn14:Fc-treated mice compared to controls. A macrophage-rich plaque phenotype was the result of a significantly increased macrophage content (Fn14:Fc 63.4±1.9% vs. control 36.3±2.7%, p<0.05) along with a significantly decreased collagen (Fn14:Fc 30.1±5.5% vs. control 41.9±3.6%, p<0.05) and smooth muscle cell content (Fn14:Fc 1.8±0.2% vs. control 4.5±0.6%, p<0.05) in advanced atherosclerotic plaques of Fn14:Fc-treated compared to control mice. To investigate the increased macrophage content observed in lesions of Fn14:Fc-treated mice, macrophages derived from bone marrow of ApoE-/- mice were treated in vitro with Fn14:Fc or control antibody and analyzed for DiI-labeled oxidized LDL (DiI-oxLDL) uptake by fluorescence activated cell sorting. Fn14:Fc-treated macrophages took up less DiI-oxLDL compared to control macrophages after 10 minutes (Fn14:Fc 673±26 vs. control 1002±24) and 30 minutes (Fn14:Fc 2879±54 vs. control 3371±125) of lipid loading. In conclusion, TWEAK inhibition induces a macrophage-rich plaque phenotype in ApoE-/- mice. Because TWEAK is involved in inflammation and can induce apoptosis, it may modulate lipid uptake and cell death in macrophages in atherosclerotic plaques.
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J. Vasc. Biol. 42, Sup:2 (2005) p54