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 3 integrin deficiency, and treatment of humans from Western populations with oral 3 integrin inhibitors increases mortality. The mechanisms responsible for these 3 integrin-associated events are unknown.

Methods and Results—Here we show that diet-induced death in 3 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, 3-replete animals transplanted with 3-deficient marrow died with Western-type high-fat feeding whereas 3-deficient animals transplanted with 3-replete marrow were rescued from diet-induced death. Transplantation with 3-deficient marrow also increased atherosclerosis. TNF expression was increased in 3-deficient macrophages and normalized by either retroviral or adenoviral reconstitution of 3 integrin expression. Treatment with the anti-TNF antibody infliximab rescued 3 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 3 integrin, acting through TNF, suppresses inflammation caused by hyperlipidemia attributable to high-fat feeding.