Abstract
HDL carries biologically active lipids such as sphingosine-1-phosphate (S1P) and stimulates a variety of cell signaling pathways in diverse cell types, which may contribute to its ability to protect against atherosclerosis. HDL and sphingosine-1-phosphate receptor agonists, FTY720 and SEW2871 triggered macrophage migration. HDL-, but not FTY720-stimulated migration was inhibited by an antibody against the HDL receptor, SR-BI, and an inhibitor of SR-BI mediated lipid transfer. HDL and FTY720-stimulated migration was also inhibited in macrophages lacking either SR-BI or PDZK1, an adaptor protein that binds to SR-BI's C-terminal cytoplasmic tail. Migration in response to HDL and S1P receptor agonists was inhibited by treatment of macrophages with sphingosine-1-phosphate receptor type 1 (S1PR1) antagonists and by pertussis toxin. S1PR1 activates signaling pathways including PI3K-Akt, PKC, p38 MAPK, ERK1/2 and Rho kinases. Using selective inhibitors or macrophages from gene targeted mice, we demonstrated the involvement of each of these pathways in HDL-dependent macrophage migration. These data suggest that HDL stimulates the migration of macrophages in a manner that requires the activities of the HDL receptor SR-BI as well as S1PR1 activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Cell Movement / drug effects
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Cells, Cultured
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Fingolimod Hydrochloride
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Lipoproteins, HDL / pharmacology*
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Macrophages / cytology*
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Macrophages / drug effects
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Macrophages / metabolism*
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Membrane Proteins
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Oxadiazoles / pharmacology
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Pertussis Toxin / pharmacology
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Propylene Glycols / pharmacology
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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Receptors, Lysosphingolipid / agonists
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Receptors, Lysosphingolipid / antagonists & inhibitors
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Receptors, Lysosphingolipid / metabolism*
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Scavenger Receptors, Class B
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Sphingosine / analogs & derivatives
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Sphingosine / pharmacology
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Thiophenes / pharmacology
Substances
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Intracellular Signaling Peptides and Proteins
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Lipoproteins, HDL
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Membrane Proteins
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Oxadiazoles
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PDZK1 protein, mouse
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Propylene Glycols
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Receptors, Lysosphingolipid
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SEW2871
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Scarb1 protein, mouse
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Scavenger Receptors, Class B
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Thiophenes
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Pertussis Toxin
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Akt1 protein, mouse
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Proto-Oncogene Proteins c-akt
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Fingolimod Hydrochloride
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Sphingosine
Grants and funding
This research was supported by a grant in aid (T 7239) and a Program Grant (PRG 6502) from the Heart and Stroke Foundation of Canada. AA is a recipient of a graduate scholarship from Kuwait University, Faculty of Medicine. LG is a recipient of a graduate scholarship from the Equal Opportunities Canada-Chile Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.