Monocyte/macrophage suppression differentially effects atherogenesis and established plaques

Abstract

Although important in atherogenesis, the role of macrophages in established plaques is contradictory. To examine this, we developed CD11b-Diphtheria toxin (DT) receptor transgenic mice, whereby administration of DT selectively kills monocyte/macrophages. DT treatment reduced peripheral blood monocytes and tissue macrophages, and inhibited macrophage function in CD11b-DTR/ApoE−/− mice and ApoE−/− mice transplanted with CD11b-DTR/ApoE−/− bone marrow. In atherogenesis studies, DT reduced plaque development in whole aortas (14.6% ± 1.8 versus 5.6% ± 1.5) and in brachiocephalic arteries (20.8% ± 3.5 versus 9% ± 2.2); and altered plaque composition, reducing collagen content (32.4% ± 4.3 versus 12.7% ± 4.1) and necrotic core size (15.4% ± 2.8 versus 9.4% ± 2.4). Acute DT treatment of mice with established plaques demonstrated macrophage apoptosis (TUNEL positive cells increased from 0.9% ± 0.3 to 3.5% ± 0.6) and reduced macrophage content (44.3% ± 3.4 versus 34.9% ± 2.9), but did not induce plaque inflammation, thrombosis or rupture. Unexpectedly, despite a 40–50% reduction in circulating monocytes, chronic DT treatment of mice with established plaques had minimal effect on plaque extent or composition. Our data suggests that a reduction in monocyte numbers during atherogenesis has a global effect on plaque development and that macrophage infiltration is a possible stimulus for VSMC recruitment, collagen synthesis and necrotic core formation. In contrast, established plaques are much more resistant to changes in monocyte numbers.