title: Differential complement activation pathways promote C3b deposition on native and acetylated LDL thereby inducing lipoprotein binding to the complement receptor 1.
abstract: Lipoproteins can induce complement activation resulting in opsonization and binding of these complexes to complement receptors. We investigated the binding of opsonized native LDL and acetylated LDL (acLDL) to the complement receptor 1 (CR1). Binding of complement factors C3b, IgM, C1q, mannose-binding lectin (MBL), and properdin to LDL and acLDL were investigated by ELISA. Subsequent binding of opsonized LDL and acLDL to CR1 on CR1-transfected Chinese Hamster Ovarian cells (CHO-CR1) was tested by flow cytometry. Both native LDL and acLDL induced complement activation with subsequent C3b opsonization upon incubation with normal human serum. Opsonized LDL and acLDL bound to CR1. Binding to CHO-CR1 was reduced by EDTA, whereas MgEGTA only reduced the binding of opsonized LDL, but not of acLDL suggesting involvement of the alternative pathway in the binding of acLDL to CR1. In vitro incubations showed that LDL bound C1q, whereas acLDL bound to C1q, IgM, and properdin. MBL did neither bind to LDL nor to acLDL. The relevance of these findings was demonstrated by the fact that ex vivo up-regulation of CR1 on leukocytes was accompanied by a concomitant increased binding of apolipoprotein B-containing lipoproteins to leukocytes without changes in LDL-receptor expression. In conclusion, CR1 is able to bind opsonized native LDL and acLDL. Binding of LDL to CR1 is mediated via the classical pathway, whereas binding of acLDL is mediated via both the classical and alternative pathways. Binding of lipoproteins to CR1 may be of clinical relevance due to the ubiquitous cellular distribution of CR1.
authors.affiliation: From the Departments of Internal Medicine, Diabetes and Vascular Center.
authors.forename: Boudewijn
authors.initials: B
authors.lastname: Klop
authors.affiliation: Department of Nephrology.
authors.forename: Pieter
authors.initials: P
authors.lastname: van der Pol
authors.affiliation: Sanquin Research, 1006 AN Amsterdam, the Netherlands.
authors.forename: Robin
authors.initials: R
authors.lastname: van Bruggen
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Einthoven Laboratory for Experimental Vascular Medicine, and.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Departments of Internal Medicine, Diabetes and Vascular Center.
authors.forename: Marijke A
authors.initials: MA
authors.lastname: de Vries
authors.affiliation: From the Departments of Internal Medicine, Diabetes and Vascular Center.
authors.forename: Selvetta
authors.initials: S
authors.lastname: van Santen
authors.affiliation: Department of Nephrology.
authors.forename: Joseph
authors.initials: J
authors.lastname: O'Flynn
authors.affiliation: Clinical Chemistry, and.
authors.forename: Gert-Jan M
authors.initials: GJ
authors.lastname: van de Geijn
authors.affiliation: Clinical Chemistry, and.
authors.forename: Tjin L
authors.initials: TL
authors.lastname: Njo
authors.affiliation: Clinical Chemistry, and.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Janssen
authors.affiliation: Medical Microbiology, Sint Franciscus Gasthuis, 3004 BA Rotterdam, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: de Man
authors.affiliation: Department of Cardiology, Leiden University Medical Center, 1006 AN Leiden, the Netherlands, and.
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.affiliation: Department of Nephrology.
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
authors.affiliation: Department of Endocrinology and Metabolic Diseases, Einthoven Laboratory for Experimental Vascular Medicine, and.
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.affiliation: Department of Nephrology.
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
authors.affiliation: From the Departments of Internal Medicine, Diabetes and Vascular Center, m.castrocabezas@sfg.nl.
authors.forename: Manuel Castro
authors.initials: MC
authors.lastname: Cabezas
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D016466:CHO Cells; D002478:Cells, Cultured; D003167:Complement Activation; D015922:Complement C1q / Q000378:metabolism; D003179:Complement C3b / Q000378:metabolism*; D003170:Complement Pathway, Alternative; D003171:Complement Pathway, Classical; D006224:Cricetinae; D003412:Cricetulus; D004492:Edetic Acid / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D009895:Opsonin Proteins / Q000378:metabolism; D011414:Properdin / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017463:Receptors, Complement 3b / Q000235:genetics / Q000378:metabolism*
chemical_list: D001055:Apolipoproteins B; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D009895:Opsonin Proteins; D017463:Receptors, Complement 3b; C032629:acetyl-LDL; D011414:Properdin; D015922:Complement C1q; D003179:Complement C3b; D004492:Edetic Acid
keywords: C3b; CR1; Complement; Complement Activation; Erythrocyte; Leukocyte; Lipoprotein; Low-density Lipoprotein (LDL); Receptor