Abstract 1736: Deficiency in Mer Receptor Tyrosine Kinase Induces Accumulation of Apoptotic Debris and Acceleration of Atherosclerosis in Mice
A well-recognized characteristic of atherosclerotic plaques is the accumulation of cell debris during plaque progression toward the advanced stages. Membranes of apoptotic cells are particularly rich in inflammatory oxidized phospholipids, suggesting that accumulation of apoptotic debris within the plaque might increase the risk of lesion progression. Here, we tested our hypothesis that mer receptor tyrosine kinase (MERTK) expression by macrophages is required for a safe clearance of apoptotic fragments from atherosclerotic plaques and substantially limits lesion development. We used a bone marrow reconstitution model to obtain the development of fatty streaks in which macrophages are deficient in MERTK. We irradiated and reconstituted low-density lipoprotein receptor deficient mice with either a wild type (CONT group) or MERTK-deficient bone marrow (MERTK−/− group). After 4 weeks of recovery, the chimeric mice were put on atherogenic diet to induce lesion development. Lesions of MERTK−/−mice showed premature and abnormal accumulation of TUNEL-positive cells and debris (25.4±8.2 % of lesion area positive for TUNEL in MERTK−/− group vs 1.6±1.1% in MERTK+/+ group; P<0.05), leading to the formation of large acellular cores. This was associated with a significant increase in lesion size at the aortic sinus level in mice reconstituted with MERTK−/−bone marrow, compared to CONT group (+66% and +39% in mice fed 8 or 15 weeks with high fat diet respectively), despite similar serum cholesterol levels. CD3-stimulated purified CD4+ T cells from MERTK−/− group showed increased interleukin-10 production (+32%, P<0.01) compared with CONT. However, increased lesion progression in MERTK−/− mice might be due to increased production of pro-atherogenic TNF-α cytokine by MERTK−/− macrophages compared with control macrophages. These findings indicate that disruption of MERTK-dependent apoptotic cell clearance by macrophages induced profound alterations in the immuno-inflammatory response and a marked acceleration of atherosclerosis. This may explain, at least in part, the high prevalence of atherosclerosis in diseases characterized by increased accumulation of apoptotic cells, such as systemic lupus erythematosus.