title: Minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells.
abstract: Minimally modified low density lipoprotein (mmLDL) is a pro-inflammatory and pro-atherogenic lipoprotein that, unlike profoundly oxidized LDL (OxLDL), is not recognized by scavenger receptors and thus does not have enhanced uptake by macrophages. However, here we demonstrate that mmLDL (as well as OxLDL) induces actin polymerization and spreading of macrophages, which results in such pro-atherogenic consequences as inhibition of phagocytosis of apoptotic cells but enhancement of OxLDL uptake. We also demonstrate for the first time that the lipopolysaccharide receptor, CD14, and toll-like receptor-4/MD-2 are involved in these mmLDL effects. Macrophages of the J774 cell line exhibited higher mmLDL binding and F-actin response than its CD14-deficient mutant, LR-9 cells. Similarly, Chinese hamster ovary cells transfected with human CD14 specifically bound mmLDL and responded with higher F-actin compared with control cells. Macrophages from C3H/HeJ mice, which have a point mutation in the Tlr4 gene, responded with lower F-actin to mmLDL and did not spread as well as macrophages from control animals. A significantly higher F-actin response was also observed in Chinese hamster ovary cells transfected with human toll-like receptor-4/MD-2 but not with TLR4 alone or TLR2. Thus, in addition to inhibition of phagocytosis, the recognition of mmLDL by macrophage lipopolysaccharide receptors results in convergence of cellular immune responses to products of microorganisms and to oxidation-specific self-antigens, which could both influence macrophage function and atherogenesis.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA. yumiller@ucsd.edu
authors.forename: Yury I
authors.initials: YI
authors.lastname: Miller
authors.forename: Suganya
authors.initials: S
authors.lastname: Viriyakosol
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Binder
authors.forename: James R
authors.initials: JR
authors.lastname: Feramisco
authors.forename: Theo N
authors.initials: TN
authors.lastname: Kirkland
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D001704:Biopolymers; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D029721:Drosophila Proteins; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D010587:Phagocytosis / Q000502:physiology*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000502:physiology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D000199:Actins; D000954:Antigens, Surface; D001704:Biopolymers; D029721:Drosophila Proteins; D018950:Lipopolysaccharide Receptors; D008077:Lipoproteins, LDL; C113553:Ly86 protein, mouse; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C099252:oxidized low density lipoprotein