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

Yıldırım C, Vogel DY, Hollander MR, Baggen JM, Fontijn RD, Nieuwenhuis S, Haverkamp A, de Vries MR, Quax PH, Garcia-Vallejo JJ, van der Laan AM, Dijkstra CD, van der Pouw Kraan TC, van Royen N, Horrevoets AJ - PLoS ONE (2015)

Bottom Line: The inhibiting effect of galectin-2 on arteriogenesis was confirmed in vivo, but the mechanism is largely unknown.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).

View Article: PubMed Central - PubMed

Affiliation: Dept of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus

Human galectin-2 stimulation of macrophages does not affect gene transcription and surface protein expression of all M2 markers.Different human monocyte-derived macrophage subtypes at day 7 were stimulated as in Fig 5. Macrophages were analyzed for the indicated M2 markers by real-time PCR (A) or flow cytometry (B). Representative histograms for CD206 expression are shown in panel B. Expression levels are expressed relative to M0 untreated samples, as in Fig 5.
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pone.0124347.g006: Human galectin-2 stimulation of macrophages does not affect gene transcription and surface protein expression of all M2 markers.Different human monocyte-derived macrophage subtypes at day 7 were stimulated as in Fig 5. Macrophages were analyzed for the indicated M2 markers by real-time PCR (A) or flow cytometry (B). Representative histograms for CD206 expression are shown in panel B. Expression levels are expressed relative to M0 untreated samples, as in Fig 5.

Mentions: To test whether galectin-2 could reduce M2 markers, we measured the effects of galectin-2 on a set of distinctive M2-expressed marker genes[17–21]i.e. mannose receptor (CD206), PDGF-C, CCL26, and CCL18. RT-PCR data showed that galectin-2 significantly reduced mRNA expression of the mannose receptor by M0- and M2 macrophages, and reduced PDGF-C in M0macrophages (Fig 6A). Galectin-2 did not significantly inhibit the expression of the other M2 markers, CCL26 and CCL18. The reduced gene expression of the mannose receptor was confirmed at the protein level by flow cytometry (Fig 6B). Collectively, these data indicate that galectin-2 can partially modify differentiated M2 macrophages to M1 macrophages.


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

Yıldırım C, Vogel DY, Hollander MR, Baggen JM, Fontijn RD, Nieuwenhuis S, Haverkamp A, de Vries MR, Quax PH, Garcia-Vallejo JJ, van der Laan AM, Dijkstra CD, van der Pouw Kraan TC, van Royen N, Horrevoets AJ - PLoS ONE (2015)

Human galectin-2 stimulation of macrophages does not affect gene transcription and surface protein expression of all M2 markers.Different human monocyte-derived macrophage subtypes at day 7 were stimulated as in Fig 5. Macrophages were analyzed for the indicated M2 markers by real-time PCR (A) or flow cytometry (B). Representative histograms for CD206 expression are shown in panel B. Expression levels are expressed relative to M0 untreated samples, as in Fig 5.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401781&req=5

pone.0124347.g006: Human galectin-2 stimulation of macrophages does not affect gene transcription and surface protein expression of all M2 markers.Different human monocyte-derived macrophage subtypes at day 7 were stimulated as in Fig 5. Macrophages were analyzed for the indicated M2 markers by real-time PCR (A) or flow cytometry (B). Representative histograms for CD206 expression are shown in panel B. Expression levels are expressed relative to M0 untreated samples, as in Fig 5.
Mentions: To test whether galectin-2 could reduce M2 markers, we measured the effects of galectin-2 on a set of distinctive M2-expressed marker genes[17–21]i.e. mannose receptor (CD206), PDGF-C, CCL26, and CCL18. RT-PCR data showed that galectin-2 significantly reduced mRNA expression of the mannose receptor by M0- and M2 macrophages, and reduced PDGF-C in M0macrophages (Fig 6A). Galectin-2 did not significantly inhibit the expression of the other M2 markers, CCL26 and CCL18. The reduced gene expression of the mannose receptor was confirmed at the protein level by flow cytometry (Fig 6B). Collectively, these data indicate that galectin-2 can partially modify differentiated M2 macrophages to M1 macrophages.

Bottom Line: The inhibiting effect of galectin-2 on arteriogenesis was confirmed in vivo, but the mechanism is largely unknown.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).

View Article: PubMed Central - PubMed

Affiliation: Dept of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus