Galectin-2 induces a proinflammatory, anti-arteriogenic phenotype in monocytes and macrophages

• Published in: PloS one Vol. 10; no. 4; p. e0124347
• Main Authors: Yıldırım, Cansu, Vogel, Daphne Y S, Hollander, Maurits R, Baggen, Josefien M, Fontijn, Ruud D, Nieuwenhuis, Sylvia, Haverkamp, Anouk, de Vries, Margreet R, Quax, Paul H A, Garcia-Vallejo, Juan J, van der Laan, Anja M, Dijkstra, Christine D, van der Pouw Kraan, Tineke C T M, van Royen, Niels, Horrevoets, Anton J G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.04.2015; Public Library of Science (PLoS)
• Subjects: Angiogenesis; Animal models; Animals; Arteries; Binding; Biology; Carbohydrates; Cardiology; Cardiovascular disease; CD14 antigen; CD40 antigen; CD40 Antigens - biosynthesis; Cell Differentiation; Cells, Cultured; Chemokines; Chromatography; Collateral Circulation - drug effects; Collateral Circulation - physiology; Coronary artery; Coronary artery disease; Cytokines; Dendritic Cells - metabolism; Galectin 2 - deficiency; Galectin 2 - genetics; Galectin 2 - pharmacology; Galectin 2 - physiology; Gene expression; Gene Expression Regulation; Genetic aspects; Glycerol; Heart diseases; Humans; Immune system; Immunology; In vivo methods and tests; Inflammation; Inflammation - physiopathology; Ischemia; Laboratories; Lectins; Lectins, C-Type - biosynthesis; Leukocyte migration; Lipopolysaccharide Receptors - immunology; Lipopolysaccharide Receptors - physiology; Macrophages; Macrophages - classification; Macrophages - drug effects; Macrophages - physiology; Mannose Receptor; Mannose-Binding Lectins - biosynthesis; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular weight; Monocytes; Monocytes - drug effects; Monocytes - physiology; Patients; Phenotype; Physicians; Protein binding; Protein Binding - drug effects; Protein interaction; Proteins; RAW 264.7 Cells; Receptors, Cell Surface - biosynthesis; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - pharmacology; Signal Transduction; T-Lymphocytes - metabolism; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Tumor necrosis factor-TNF; Vascular endothelial growth factor; Vascular surgery
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0124347

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.