Quantitative and qualitative contribution of splenic monocytes to plaque development

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Atherosclerosis is a chronic inflammatory disease in which particularly monocytes play a crucial role. They infiltrate plaques, differentiate into macrophages and dendritic cells and promote all stages of atherosclerosis from initiation to complication. Until recently monocytes were regarded as mere transitory cells, that extravasate from blood into inflamed tissue to differentiate into local effector cells. Surprisingly, however, Swirski et al. recently showed, that undifferentiated monocytes accumulate and reside in the spleen. In acute myocardial infarction splenic monocytes infiltrate the ischemic regions substantially and contribute to myocardial damage. This scientific grant application aims to explore the specific role of splenic monocytes in atherogenesis by addressing the following questions: 1. Which percentage of monocytes infiltrating atherosclerotic plaques originates from the spleen? 2. Are splenic monocytes in murine atherosclerosis functionally distinct from circulating monocytes released from the bone marrow? 3. Do splenic monocytes ultimatively and distinctly modulate plaque progression and plaque stability? We propose two complementary approaches. We compare atherosclerotic aortas from splenectomized ApoE-/- mice with respective controls. Secondly, CD45.2+ donor spleens are transplanted into CD45.1+ recipients in order to track plaque infiltration of CD45.2+ splenic monocytes as well as their differentiation into macrophages and dendritic cells at different time points. This will allow us to evaluate the influence of splenic monocytes on plaque composition. Methods include classical cell and molecular biology tools and non-invasive imaging techniques in vivo. The goal of this proposal is to gain a better understanding of monocyte biology in the context of atherosclerosis, ultimately paving the way for the development of novel therapeutic approaches.