Abstract | 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.
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Authors | Guangyu An, Huan Wang, Rong Tang, Tadayuki Yago, J Michael McDaniel, Samuel McGee, Yuqing Huo, Lijun Xia |
Journal | Circulation
(Circulation)
Vol. 117
Issue 25
Pg. 3227-37
(Jun 24 2008)
ISSN: 1524-4539 [Electronic] United States |
PMID | 18519846
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Monoclonal
- Antigens, Ly
- Apolipoproteins E
- E-Selectin
- Ly-6C antigen, mouse
- Membrane Glycoproteins
- P-Selectin
- P-selectin ligand protein
- RNA, Messenger
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Topics |
- Animals
- Antibodies, Monoclonal
(immunology)
- Antigen-Antibody Reactions
- Antigens, Ly
(biosynthesis)
- Apolipoproteins E
(deficiency)
- Atherosclerosis
(genetics, immunology)
- Binding Sites
- Carotid Artery Injuries
(genetics, immunology)
- Cell Adhesion
(immunology)
- Chemotaxis, Leukocyte
(immunology)
- Disease Models, Animal
- E-Selectin
(metabolism)
- Flow Cytometry
- Membrane Glycoproteins
(biosynthesis, deficiency, genetics)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Monocytes
(immunology)
- P-Selectin
(metabolism)
- RNA, Messenger
(genetics)
- Reverse Transcriptase Polymerase Chain Reaction
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