Abstract 135: Exploration and Modulation of TREM-1 in Experimental Atherosclerosis

Under conditions of atherosclerosis, monocytes are rapidely recruited into the vessel wall where they differentiate into macrophages. Both classical and nonclassical monocytes are continuously recruited to the lesion and contribute to atherosclerosis formation. Whereas the number of circulating monocytes correlates with plaque development, decrease in their number or migration is protective. Upon differentiation, macrophages increase TLR expression, which triggers the inflammatory response. The triggering receptor expressed on myeloid cells (TREM-1) has been shown to amplify TLR-induced signals in sepsis or inflammatory bowel disease. TREM-1 is also produced in a soluble form and is a predictive factor during sever infections in humans. We addressed for the first time the role of TREM-1 in atherosclerosis. We found preferential expression of TREM-1 on blood neutrophils and nonclassical monocytes in both ApoE+/+ and ApoE-/- mice, but sTREM-1 was only detectable in plasma of ApoE-/- mice (ELISA). TREM-1 expression was significantly increased on both cell types in APOE-/- mice after 4 weeks of high fat diet (Flow cytometry). We next addressed the role of TREM-1 in atherosclerosis formation by injection of a TREM-like transcript 1-derived peptide (LR12) in 8 week-old ApoE-/- mice (daily injection for 4 weeks of LR12 or peptide scramble as control). We found that pharmaceutical inhibition of TREM-1 significantly reduced plaque formation by 30% without change in cholesterol levels. This was associated with significant reduction in macrophage accumulation after treatment with LR12 (57735,34 μm2 vs 78398,38 μm2 in controls; p=0,004). We demonstrated that LR12 treatment induced a specific rapid and sustained decrease in circulating nonclassical monocytes after 7 days of treatment. By using an in vivo pulse labeling method to quantify monocyte migration, we found that LR12 also altered nonclassical monocyte recruitment to the plaque. Taken together, these data indicate that TREM-1 expression increases in the context of atherosclerosis and that pharmacological inhibition of TREM-1 protects against plaque development through decreased number and infiltration of nonclassical monocytes.