Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion.

Abstract

Macrophages drive atherosclerotic plaque progression and rupture; hence, attenuating their atherosclerosis-inducing properties holds promise for reducing coronary heart disease (CHD). Recent studies in mouse models have demonstrated that Tribbles 1 (Trib1) regulates macrophage phenotype and shows that <i>Trib1</i> deficiency increases plasma cholesterol and triglyceride levels, suggesting that reduced <i>TRIB1</i> expression mediates the strong genetic association between the <i>TRIB1</i> locus and increased CHD risk in man. However, we report here that myeloid-specific <i>Trib1</i> (m<i>Trib1</i>) deficiency reduces early atheroma formation and that m<i>Trib1</i> transgene expression increases atherogenesis. Mechanistically, m<i>Trib1</i> increased macrophage lipid accumulation and the expression of a critical receptor (OLR1), promoting oxidized low-density lipoprotein uptake and the formation of lipid-laden foam cells. As <i>TRIB1</i> and <i>OLR1</i> RNA levels were also strongly correlated in human macrophages, we suggest that a conserved, TRIB1-mediated mechanism drives foam cell formation in atherosclerotic plaque and that inhibiting mTRIB1 could be used therapeutically to reduce CHD.