Abstract 1513: Lactadherin-Dependent Phagocytosis of Apoptotic Cells is Required for a Protective Immune Response in Atherosclerosis
Atherosclerosis is a potentially fatal immuno-inflammatory disease of the arterial wall elicited in response to oxidized (phospho)lipids. Recent studies have clearly shown that the control of the pathogenic immune response in atherosclerosis is required to limit disease development. However, the key factors responsible for the maintenance of immune regulation in a pro-inflammatory hypercholesterolemic milieu, are poorly understood. Here, we show that phagocytic clearance of apoptotic cells by professional scavengers expressing the milk fat globule-EGF Factor 8 (Mfge8, also known as lactadherin) is required for a protective immune response in atherosclerosis. Mfge8 was expressed in normal human arteries within endothelial cells, smooth muscle cells and macrophages but its expression was lower in foam-cell macrophages located within the lipid-rich core. LDLr−/ − mice were irradiated and reconstituted with either Mfge8−/ − bone marrow (Mfge8/LDLr KO) or wild type bone marrow. After 8 weeks of high fat diet, Mfge8/LDLr KO mice showed 70% increase of plaque size in the aortic sinus (P=0.005) with premature accumulation of TUNEL-positive cells and debris, compared to LDLr KO mice with wild type bone marrow. This was associated with a 4-fold increase of acellular core area (P<0.001). After 15 weeks of high fat diet, Mfge8/LDLr KO mice showed 38% increase of plaque size (P<0.05) with significant accumulation of TUNEL-positive cells and debris. Using quantitative RT-PCR, we found a profound decrease in IL10 mRNA expression but a significant increase in IFNγ levels in the spleens of Mfge8/LDLr KO mice compared to controls. In vitro, splenocytes and CD4+ T cells from Mfge8/LDLr KO mice showed a decrease in IL10 production. Co-culture of effector and regulatory CD4+ cells in the presence of dendritic cells revealed a dendritic cell-dependent alteration of regulatory T cell suppressive function in Mfge8/LDLr KO mice. In conclusion, efficient Mfge8-dependent clearance of apoptotic cells promotes a protective immune response in atherosclerosis and critically controls lesion development.