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 TNFα-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. TNFα expression was increased in β3-deficient macrophages and normalized by either retroviral or adenoviral reconstitution of β3 integrin expression. Treatment with the anti-TNFα antibody infliximab rescued β3 integrin–deficient mice from Western diet–induced death, directly implicating TNFα in the pathophysiology triggered by diet-induced hyperlipidemia.

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