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