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: Cansu Yıldırım, Daphne Y S Vogel, Maurits R Hollander, Josefien M Baggen, Ruud D Fontijn, Sylvia Nieuwenhuis, Anouk Haverkamp, Margreet R de Vries, Paul H A Quax, Juan J Garcia-Vallejo, Anja M van der Laan, Christine D Dijkstra, Tineke C T M van der Pouw Kraan, Niels van Royen, Anton J G Horrevoets
• Journal: PloS one (PLoS One) Vol. 10 Issue 4 Pg. e0124347 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25884209 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD40 Antigens
• Galectin 2
• Lectins, C-Type
• Lipopolysaccharide Receptors
• Mannose Receptor
• Mannose-Binding Lectins
• Receptors, Cell Surface
• Recombinant Fusion Proteins
• TLR4 protein, human
• Tlr4 protein, mouse
• Toll-Like Receptor 4

Topics

• Animals
• CD40 Antigens (biosynthesis)
• Cell Differentiation
• Cells, Cultured
• Collateral Circulation (drug effects, physiology)
• Dendritic Cells (metabolism)
• Galectin 2 (deficiency, genetics, pharmacology, physiology)
• Gene Expression Regulation
• Humans
• Inflammation (physiopathology)
• Lectins, C-Type (biosynthesis)
• Lipopolysaccharide Receptors (immunology, physiology)
• Macrophages (classification, drug effects, physiology)
• Mannose Receptor
• Mannose-Binding Lectins (biosynthesis)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Monocytes (drug effects, physiology)
• Phenotype
• Protein Binding (drug effects)
• RAW 264.7 Cells
• Receptors, Cell Surface (biosynthesis)
• Recombinant Fusion Proteins (metabolism, pharmacology)
• Signal Transduction
• T-Lymphocytes (metabolism)
• Toll-Like Receptor 4 (metabolism)