Cell type-specific roles of integrin CD11b in atherosclerosis regression - Atherosclerosis is a disease of the arteries, with estimated health care costs around $400 billion in the US alone in 2020, which are expected to triple to $1344 billion in 2050. Current lipid-lowering therapies are effective at preventing the progression of atherosclerosis but are ineffective (~1%) at inducing plaque regression. Given that a 1% reduction in plaque burden leads to a 20% reduction in the odds of cardiovascular diseases, the development of new therapies that facilitate more efficient plaque regression is urgently needed. The regression of atherosclerosis is a complex process that involves the clearance of cellular debris and cholesterol/lipid deposits, as well as the removal of foam cells and proinflammatory macrophages, which is largely mediated by non-foam cell macrophages. CD11b/CD18 (Mac-1 or αMβ2) is an integrin receptor highly expressed on macrophages, yet its function in atherosclerosis regression remains poorly understood. Our preliminary results revealed that the deletion of CD11b in LDLR−/− mice promotes the development of atherosclerosis under hyperlipidemia, indicating that CD11b possesses novel atheroprotective functions. Using CD11b-floxed mice, we discovered that this beneficial function of CD11b/CD18 is associated with resident macrophages. Crucially, our preliminary data further revealed that CD11b/CD18 is essential for atherosclerosis regression in LDLR−/− mice following the re-expression of LDLR. Mechanistically, we discovered that CD11b possesses novel anti-inflammatory properties. Our recent preliminary data unveiled novel interactions between CD11b/CD18, ATP-binding cassette transporter A1 (ABCA1), and Apolipoprotein A-1 (ApoA1), and they also identified a key role of CD11b/CD18 in ABCA1-mediated cholesterol efflux from macrophages to HDL particles. Based on these exciting preliminary results, we hypothesize that macrophage-specific CD11b, in conjunction with ABCA1, promotes atherosclerosis regression by suppressing vascular inflammation and enhancing cholesterol and lipid removal from the atherosclerotic plaques. To test this hypothesis, we generated a reverse floxed ApoE−/− (revApoEKO) mouse model, where tamoxifen-induced re-expression of ApoE results in significant plaque regression. We propose three Specific Aims in this application. In Specific Aim 1, we will examine the role of cell type-specific CD11b/CD18 in atherosclerosis regression and investigate the reversibility of atherosclerosis at various stages of disease development. In Specific Aim 2, we will elucidate the molecular mechanisms by which a ternary complex of CD11b/CD18, ABCA1, and ApoA1 enhances cholesterol efflux efficiency. In Specific Aim 3, we will explore novel CD11b-targeting strategies to promote atherosclerosis regression using two independent mouse models: LDLR−/− mice and revApoEKO mice. Completion of this project will provide valuable insights into how CD11b/CD18, together with ABCA1 and ApoA1, enhances the effectiveness of atherosclerosis regression following lipid-lowering therapy, ultimately reducing the risk of cardiovascular diseases.
