Abstract 876: Combined Inhibition Of Ccl2, Cx3cr1 And Ccr5 Abrogates Ly6chi And Ly6clo Monocytosis And Almost Abolishes Atherosclerosis In Hypercholesterolemic Mice
Monocytes are critical mediators of atherogenesis. Specialized chemokine/chemokine receptor pathways orchestrate the infiltration of specific monocyte subsets within atherosclerotic arteries. Interruption of individual chemokine pathways including CCL2/CCR2, CCL5/CCR5, CX3CL1/CX3CR1, CXCL8/CXCR2 or CXCL10/CXCR3, leads to significant but only partial inhibition of lesion development, whereas deficiency in other signals such as CXCL16 or CCR1 accelerates atherosclerosis. Evidence that particular chemokine pathways may cooperate to promote monocyte recruitment into atherosclerotic arteries is still lacking. Here, we show that in addition to the current prevailing paradigm accounting for the role of chemokines as modulators of monocyte trafficking between the blood and the vessel wall, chemokine-mediated signals critically determine the frequency of monocytes in the blood and the bone marrow under both non-inflammatory and atherosclerotic conditions. Particularly, CCL2, CX3CR1 and CCR5-dependent signals differentially alter CD11b+ Ly6G- 7/4hi (also known as Ly6Chi) and CD11b + Ly6G- 7/4lo (Ly6Clo) monocytosis. Combined inhibition of these pathways in hypercholesterolemic, atherosclerosis susceptible apolipoprotein E-deficient mice leads to additive reduction in bone marrow and circulating monocytes, associated with a marked and additive 90% reduction in atherosclerosis. Lesion size highly correlates with the number of circulating monocytes. Thus, signals mediated through CCL2, CX3CR1 and CCR5 critically determine the frequency of circulating monocyte subsets and thereby account for almost all macrophage accumulation into atherosclerotic arteries.