Abstract 872: Adhesion Molecule CD44 may Impair Atherosclerotic Cell Recruitment through its Influence on Chemokine Receptor 5
Atherogenesis involves recruitment of inflammatory cells to the growing lesion. CD44 is an adhesion molecule expressed on vascular and inflammatory cells. We have shown that CD44 is greatly increased in human atherosclerotic lesions and its appearance enhanced by pro-inflammatory cytokines. In addition, CD44 levels correlate with augmented macrophage IL-6 secretion, which has great import for atherogenesis since IL-6 participates in leukocyte trafficking. Our recent data suggest that mice lacking LDL-receptors exhibit 50% fewer plaque T-cells after CD44-deficient (Cd44−/−) bone marrow transplantation (P=0.003, n=12). This was not due to inadequate endogenous T-cell production, since both Cd44−/− and wild-type mice exhibit similar leukocyte counts. Here, we assessed the hypothesis that chemokine receptor 5 (CCR5) influences inflammatory cell accumulation in the atherosclerotic plaque through a CD44-mediated mechanism, and addressed a possible connection between CCR5, CD44, and IL-6. CCR5 is expressed on macrophages, T-cells, and dendritic cells and mediates leukocyte attraction into developing lesions. We found that CCR5 expression by Cd44−/− inflammatory cells (i.e. T-cells and macrophages) is impaired; peritoneal macrophages exhibited 30% reduction (P<0.05, n=8) and T-cells 40% reduction (P<0.05, n=3) in CCR5 expression. IL-6 at pathological levels (500 pg/mL) stimulated macrophage CCR5 (2-fold, n=2). Interestingly, atherosclerotic patients with elevated CD44 expression exhibit enhanced levels of macrophage CCR5 mRNA (microarray intensity signal 396±34 vs. 314±15, P=0.038, n=15) and protein (2-fold increase, n=2) compared to healthy controls. In conclusion, these studies suggest that CCR5 expression is influenced by the presence of adhesion molecule CD44 and the pro-inflammatory cytokine IL-6. Thus, CCR5 may contribute to T-cell and macrophage recruitment into the growing atherosclerotic lesion.