P-selectin glycoprotein ligand-1 is highly expressed on ly-6Chi monocytes and a major determinant for ly-6Chi monocyte recruitment to sites of atherosclerosis in mice

Background - Ly-6C monocytes are key contributors to atherosclerosis in mice. However, the manner in which Ly-6C monocytes selectively accumulate in atherosclerotic lesions is largely unknown. Monocyte homing to sites of atherosclerosis is primarily initiated by rolling on P- and E-selectin expressed on endothelium. We hypothesize that P-selectin glycoprotein ligand-1 (PSGL-1), the common ligand of P- and E-selectin on leukocytes, contributes to the preferential homing of Ly-6C monocytes to atherosclerotic lesions. Methods and Results - To test this hypothesis, we examined the expression and function of PSGL-1 on Ly-6C and Ly-6C monocytes from wild-type mice, ApoE mice, and mice lacking both ApoE and PSGL-1 genes (ApoE/PSGL-1). We found that Ly-6C monocytes expressed a higher level of PSGL-1 and had enhanced binding to fluid-phase P- and E-selectin compared with Ly-6C monocytes. Under in vitro flow conditions, more Ly-6C monocytes rolled on P-, E-, and L-selectin at slower velocities than Ly-6C cells. In an ex vivo perfused carotid artery model, Ly-6C monocytes interacted preferentially with atherosclerotic endothelium compared with Ly-6C monocytes in a PSGL-1-dependent manner. In vivo, ApoE mice lacking PSGL-1 had impaired Ly-6C monocyte recruitment to atherosclerotic lesions. Moreover, ApoE/PSGL-1 mice exhibited significantly reduced monocyte infiltration in wire injury-induced neointima and in atherosclerotic lesions. ApoE/PSGL-1 mice also developed smaller neointima and atherosclerotic plaques. Conclusions - These data indicate that PSGL-1 is a new marker for Ly-6C monocytes and a major determinant for Ly-6C cell recruitment to sites of atherosclerosis in mice.