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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2699.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Macrophage β3 Integrin Suppresses Hyperlipidemia-Induced Inflammation by Modulating TNF Expression

Jochen G. Schneider; Yimin Zhu; Trey Coleman; Clay F. Semenkovich

From the Department of Medicine, Division of Endocrinology, Metabolism & Lipid Research (J.G.S, Y.Z., T.C., C.F.S.), and the Department of Cell Biology & Physiology (C.F.S.), Washington University School of Medicine, St. Louis, MO.

Correspondence to Clay F. Semenkovich, MD, Campus Box 8127, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110. Email csemenko{at}wustl.edu

Objective— High-fat, cholesterol-containing diets contribute to hyperlipidemia. Both high-fat diets and hyperlipidemia are associated with chronic inflammatory diseases like atherosclerosis. Integrins, heterodimeric mediators of inflammatory cell recruitment, are not generally thought to be affected by diet. However, high-fat feeding promotes inflammation, atherosclerosis, and death in hyperlipidemic mice with β3 integrin deficiency, and treatment of humans from Western populations with oral β3 integrin inhibitors increases mortality. The mechanisms responsible for these β3 integrin-associated events are unknown.

Methods and Results— Here we show that diet-induced death in β3 integrin-deficient mice is a TNF-dependent process mediated by bone marrow–derived cells. In 2 different hyperlipidemic models, apoE-null and LDL receptor–null mice, β3-replete animals transplanted with β3-deficient marrow died with Western-type high-fat feeding whereas β3-deficient animals transplanted with β3-replete marrow were rescued from diet-induced death. Transplantation with β3-deficient marrow also increased atherosclerosis. TNF expression was increased in β3-deficient macrophages and normalized by either retroviral or adenoviral reconstitution of β3 integrin expression. Treatment with the anti-TNF antibody infliximab rescued β3 integrin–deficient mice from Western diet–induced death, directly implicating TNF in the pathophysiology triggered by diet-induced hyperlipidemia.

Conclusions— These findings suggest that macrophage β3 integrin, acting through TNF, suppresses inflammation caused by hyperlipidemia attributable to high-fat feeding.

The signals linking hyperlipidemia and the chronic inflammation characteristic of atherosclerosis are unknown. Here we demonstrate that the β3 integrin on macrophages suppresses diet-induced inflammation in hyperlipidemic mice by decreasing expression of TNF. Promoting anti-inflammatory signaling mediated by the β3 integrin could represent a novel treatment strategy for atherosclerosis.

Key Words: integrins • TNF • diet • bone marrow transplantation • atherosclerosis • infliximab