Background— Ly-6C^hi monocytes are key contributors to atherosclerosis in mice. However, the manner in which Ly-6C^hi 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^hi monocytes to atherosclerotic lesions.

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