Ox-LDL induces monocyte-to-macrophage differentiation in vivo: Possible role for the macrophage colony stimulating factor receptor (M-CSF-R).
Monocyte-to-macrophage differentiation and LDL oxidation play a pivotal role in early atherogenesis. We thus questioned possible mechanisms for oxidized LDL (Ox-LDL)-induced monocyte-to-macrophage differentiation in vivo. Mouse peritoneal mononuclear cells, that were isolated 1, 2, or 3 days after Ox-LDL intraperitoneal injection, gradually exhibited the characteristic macrophage morphology, along with the expression of the cell-surface antigen CD11b. Molecular mechanisms involved in Ox-LDL-induced differentiation were further investigated in vitro using the THP-1 monocytic cell line. THP-1 cells incubated with Ox-LDL in the presence of as low as 1 ng/ml of PMA differentiated into macrophages, as evidenced by morphologic, phenotypic, and functional properties. Stimulation of monocyte-to-macrophage differentiation was selective to Ox-LDL (and not native LDL), was dependent on the extent of LDL oxidation, and required Ox-LDL internalization by the cells. These effects of Ox-LDL could be attributed to its major oxysterols, 7-ketocholesterol and 7beta-hydroxycholesterol. Finally, the stimulation of monocyte differentiation to macrophages by Ox-LDL was shown to require the M-CSF-receptor, since blocking the binding to the receptor abolished Ox-LDL/7beta-hydroxycholesterol-induced differentiation. Furthermore, Ox-LDL/7beta-hydroxycholesterol elicited tyrosine phosphorylation and activation of the M-CSF-R. We thus conclude that Ox-LDL induces monocyte differentiation to macrophages in vivo and this phenomenon involves activation of the M-CSF-receptor.
The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa 31096, Israel. Fuhrman@tx.technion.ac.il
Bianca
B
Fuhrman
Ayelet
A
Partoush
Nina
N
Volkova
Michael
M
Aviram
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000166:cytology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000502:physiology*
D006888:Hydroxycholesterols; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; C011724:cholest-5-en-3 beta,7 alpha-diol; D016186:Receptor, Macrophage Colony-Stimulating Factor