P-Selectin Glycoprotein Ligand-1 Is Highly Expressed on Ly-6C Monocytes and a Major Determinant for Ly-6C 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 Pand E-selectin expressed on endothelium. We hypothesize that P-selectin glycoprotein ligand-1 (PSGL-1), the common ligand of Pand 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 Pand 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. (Circulation. 2008;117:3227-3237.)