P-Selectin Glycoprotein Ligand-1 Is Highly Expressed on Ly-6ChiMonocytes and a Major Determinant for Ly-6ChiMonocyte Recruitment to Sites of Atherosclerosis in Mice

Abstract

Background—Ly-6C^himonocytes are key contributors to atherosclerosis in mice. However, the manner in which Ly-6C^himonocytes 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^himonocytes to atherosclerotic lesions.Methods and Results—To test this hypothesis, we examined the expression and function of PSGL-1 on Ly-6C^hiand Ly-6C^lomonocytes from wild-type mice,ApoE^−/−mice, and mice lacking bothApoEandPSGL-1genes (ApoE^−/−/PSGL-1^−/−). We found that Ly-6C^himonocytes expressed a higher level of PSGL-1 and had enhanced binding to fluid-phase P- and E-selectin compared with Ly-6C^lomonocytes. Under in vitro flow conditions, more Ly-6C^himonocytes rolled on P-, E-, and L-selectin at slower velocities than Ly-6C^locells. In an ex vivo perfused carotid artery model, Ly-6C^himonocytes interacted preferentially with atherosclerotic endothelium compared with Ly-6C^lomonocytes in a PSGL-1–dependent manner. In vivo,ApoE^−/−mice lacking PSGL-1 had impaired Ly-6C^himonocyte 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^himonocytes and a major determinant for Ly-6C^hicell recruitment to sites of atherosclerosis in mice.