Fn14-Fc fusion protein regulates atherosclerosis in ApoE-/- mice and inhibits macrophage lipid uptake in vitro

Kitty Schapira, Linda C Burkly, Timothy S Zheng, Ping Wu, Mathijs Groeneweg, Mat Rousch, Mark M Kockx, Mat J A P Daemen, Sylvia Heeneman
Arteriosclerosis, Thrombosis, and Vascular Biology 2009, 29 (12): 2021-7

OBJECTIVE: TWEAK is a multifunctional cytokine belonging to the tumor necrosis factor superfamily and binds to the receptor Fn14. TWEAK and Fn14 are expressed in atherosclerotic plaques in areas rich in macrophages and foam cells. We investigated the role of TWEAK/Fn14 interactions in ApoE(-/-) mice and bone marrow-derived macrophages in vitro.

METHODS AND RESULTS: ApoE(-/-) mice were treated with TWEAK-inhibiting fusion protein, Fn14-Fc, in an early (5 to 17 weeks of age) or delayed (17 to 29 weeks of age) setting. In the aortic arch, Fn14-Fc as compared to control treatment resulted in advanced plaques which were smaller (early treatment), fewer (delayed treatment), lower in fibrotic content (early and delayed treatment), and exhibited an increased macrophage content and smaller macrophage size (delayed treatment). There were no differences in apoptosis in atherosclerotic plaques after Fn14-Fc versus control Ab treatment. However, blocking TWEAK resulted in less macrophage uptake of modified lipids in vitro.

CONCLUSIONS: Fn14-Fc fusion protein treatment did not prevent lesion initiation but inhibited some features of plaque progression and induced a unique advanced plaque phenotype with increased macrophage content and smaller macrophage size, which may be attributable to reduced lipid uptake. These findings indicate that TWEAK/Fn14 interactions regulate atherosclerosis and mediate lipid uptake in macrophages.

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