Abstract 20705: Metallophilic Macrophage Ablation Stabilizes Atherosclerotic Plaques in Mice
Sialoadhesin or CD169 is expressed on a subset of differentiated metallophilic macrophages in the marginal zone of spleen under normal conditions and at inflammation sites in rheumatoid arthritis and atherosclerosis. This subset is highly effective in clearing apoptotic cells, leading to potent suppression of T-cell responses to epitopes present in apoptotic cells. Given the proposed role of apoptotic cell clearance and autoimmunity in atherosclerosis, we evaluated the effects of ablation of this subset on advanced atherosclerotic plaques. Female LDLr−/− mice were lethally irradiated and reconstituted with bone marrow from syngenic CD169-hDTR donors with transgenic expression of human diphtheria toxin (DT) receptor under control of the CD169 promoter. After recovery and 8 weeks of Western type diet, animals were injected 6 times with DT or inactive DT (10μg/kg) every 3 days to ablate CD169+macrophages. Mice were sacrificed, either 3 days (baseline) or two weeks after the last DT-injection (recovery) and lesions were analyzed. Intriguingly, DT treatment neither affected plaque size, fibrous cap thickness nor SMC-content. In contrast, CD169+ cell depletion increased necrotic core size (38 vs 32%, P=0.018) and apoptotic cell content (4-fold, P=8E-11) at baseline, but both parameters normalized after recovery. Moreover, DT treatment led to a significant reduction in MAC3+ macrophage content at baseline and after recovery (+130%, P=0.009 and +100%, P=0.01, respectively), illustrating effective ablation of plaque macrophages. This reduction in macrophage content was accompanied by an increase in collagen content (11 vs 6%, P=0.0004). In conclusion, we are the first to show that selective ablation of CD169+ metallophilic macrophages in advanced atherosclerosis leads to reduced macrophage content and a concomitant increase in collagen content, changes that are generally deemed beneficial for plaque stability.
- © 2010 by American Heart Association, Inc.