title: Galectin-2 induces a proinflammatory, anti-arteriogenic phenotype in monocytes and macrophages.
abstract: Galectin-2 is a monocyte-expressed carbohydrate-binding lectin, for which increased expression is genetically determined and associated with decreased collateral arteriogenesis in obstructive coronary artery disease patients. The inhibiting effect of galectin-2 on arteriogenesis was confirmed in vivo, but the mechanism is largely unknown. In this study we aimed to explore the effects of galectin-2 on monocyte/macrophage phenotype in vitro and vivo, and to identify the receptor by which galectin-2 exerts these effects. We now show that the binding of galectin-2 to different circulating human monocyte subsets is dependent on monocyte surface expression levels of CD14. The high affinity binding is blocked by an anti-CD14 antibody but not by carbohydrates, indicating a specific protein-protein interaction. Galectin-2 binding to human monocytes modulated their transcriptome by inducing proinflammatory cytokines and inhibiting pro-arteriogenic factors, while attenuating monocyte migration. Using specific knock-out mice, we show that galectin-2 acts through the CD14/toll-like receptor (TLR)-4 pathway. Furthermore, galectin-2 skews human macrophages to a M1-like proinflammatory phenotype, characterized by a reduced motility and expression of an anti-arteriogenic cytokine/growth factor repertoire. This is accompanied by a switch in surface protein expression to CD40-high and CD206-low (M1). In a murine model we show that galectin-2 administration, known to attenuate arteriogenesis, leads to increased numbers of CD40-positive (M1) and reduced numbers of CD206-positive (M2) macrophages surrounding actively remodeling collateral arteries. In conclusion galectin-2 is the first endogenous CD14/TLR4 ligand that induces a proinflammatory, non-arteriogenic phenotype in monocytes/macrophages. Interference with CD14-Galectin-2 interaction may provide a new intervention strategy to stimulate growth of collateral arteries in genetically compromised cardiovascular patients.
authors.affiliation: Dept of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Cansu
authors.initials: C
authors.lastname: Yıldırım
authors.affiliation: Dept of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Daphne Y S
authors.initials: DY
authors.lastname: Vogel
authors.affiliation: Dept of Cardiology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Maurits R
authors.initials: MR
authors.lastname: Hollander
authors.affiliation: Dept of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Josefien M
authors.initials: JM
authors.lastname: Baggen
authors.affiliation: Dept of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Ruud D
authors.initials: RD
authors.lastname: Fontijn
authors.affiliation: Dept of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Nieuwenhuis
authors.affiliation: Dept of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Anouk
authors.initials: A
authors.lastname: Haverkamp
authors.affiliation: Dept of Vascular Surgery, Einthoven Laboratories, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Margreet R
authors.initials: MR
authors.lastname: de Vries
authors.affiliation: Dept of Vascular Surgery, Einthoven Laboratories, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Paul H A
authors.initials: PH
authors.lastname: Quax
authors.affiliation: Dept of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Garcia-Vallejo
authors.affiliation: Dept of Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Anja M
authors.initials: AM
authors.lastname: van der Laan
authors.affiliation: Dept of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Christine D
authors.initials: CD
authors.lastname: Dijkstra
authors.affiliation: Dept of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Tineke C T M
authors.initials: TC
authors.lastname: van der Pouw Kraan
authors.affiliation: Dept of Cardiology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: van Royen
authors.affiliation: Dept of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Anton J G
authors.initials: AJ
authors.lastname: Horrevoets
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation; D002478:Cells, Cultured; D003097:Collateral Circulation / Q000187:drug effects / Q000502:physiology*; D003713:Dendritic Cells / Q000378:metabolism; D037501:Galectin 2 / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D037181:Lectins, C-Type / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000276:immunology / Q000502:physiology; D008264:Macrophages / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects; D000067996:RAW 264.7 Cells; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D037501:Galectin 2; D037181:Lectins, C-Type; D018950:Lipopolysaccharide Receptors; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4