Abstract
Atherosclerosis, the hardening and narrowing of the arteries, is a chronic inflammatory disease driven by a crosstalk of signaling molecules between circulating immune cells and the vessel wall. In the classic view of this cardiovascular disease, hyperlipidemia initiates an inflammatory cascade that promotes macrophage infiltration into the vessel wall leading to a feedback mechanism which exacerbates lesion growth and ultimately, atherothrombosis. Our laboratory has characterized a novel atherosclerotic mice model, in which deletion of the platelet receptor Triggering Receptor Expressed on Myeloid Cells (TREM)-Like Transcript-1 (TLT-1) on a apolipoprotein E ( apoe -/- /treml1 -/- ) background dampens early macrophage infiltration into the vessel wall. This leads to decreased lesion size, instability, and calcification of atherosclerotic lesions. We have demonstrated that one of the mechanisms for dampened lesion progression is decreased platelet activation and we hypothesize that the macrophage infiltration differences may also be due to fundamental differences in macrophage phenotypic functions. In order to further define the mechanism by which TLT-1 modulates macrophage infiltration, we analyzed macrophage function in vitro . Analysis of bone marrow-derived macrophages (BMDM) from apoe -/- /treml1 -/- and apoe -/- /treml1 -/+ mice revealed no significant differences in the phagocytic function of long chain fatty acids. However, analysis of basal levels of monocyte chemoattractant protein-1 (MCP1), a key chemokine regulating monocyte infiltration, were significantly decreased in the apoe -/- /treml1 -/- BMDM supernatants. Accordingly, levels of Interleukin 6 (IL6) and Interleukin 10 (IL10) were significantly decreased in the apoe -/- /treml1 -/- BMDM supernatants after two hours of lipopolysaccharide (LPS) stimulation (p<0.05; n=5-8). These findings define an underlying difference in the BMDM secretory phenotype of the apoe -/- /treml1 -/- mice. However, it also opens the possibility of treml1 expression in macrophages, which may account for these differences. We will now investigate if an alternate isoform of treml1 is expressed in macrophages or at some period of their differentiation.
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