title: High glucose induces upregulation of scavenger receptors and promotes maturation of dendritic cells.
abstract: BACKGROUND
  Both hyperglycaemia and dendritic cells (DCs) play causative roles in atherosclerosis. However, whether they interact in atherosclerosis remains uncertain. Therefore, we examined whether high glucose could regulate the expression of scavenger receptors responsible for oxidised low-density lipoprotein (oxLDL) uptake in DCs, a critical step in atherogenesis. In addition, we investigated the impact of glucose on DC maturation regarding changes in phenotype and cytokine secretion.
  
  
  METHODS
  Immature DCs were cultured with different concentrations of glucose (5.5 mmol/L, 15 mmol/L, 30 mmol/L) in the absence or presence of N-acetylcysteine (NAC), SB203580 or Bay11-7082 for 24 hours. We used 30 mmol/L mannitol as a high-osmolarity control treatment. The expression of the scavenger receptors SR-A, CD36 and LOX-1 was determined by real-time PCR and western blot analysis. Furthermore, DCs were incubated with DiI-labelled oxLDL. The DiI-oxLDL-incorporated fraction was investigated by flow cytometry analysis. The intracellular production of ROS in DCs was measured by dichlorodihydrofluorescein (DCF) fluorescence using confocal microscopy. Finally, flow cytometry analysis was used to investigate immunophenotypic protein expression (CD83 and CD86). Supernatant cytokine measurements were used for immune function assays.
  
  
  RESULTS
  The incubation of DCs with glucose enhanced, in a dose-dependent manner, the gene and protein expression of SR-A, CD36 and LOX-1. This effect was partially abolished by NAC, SB203580 and Bay11-7082. Incubation of DCs with mannitol (30 mmol/L) did not enhance these scavenger receptors' expression. High glucose upregulated the production of ROS and expression of p38 MAPK in DCs. NAC partially reversed p38 MAPK upregulation. High glucose increased the oxLDL-uptake capacity of DCs. Blockage of the scavenger receptors SR-A and CD36 reduced oxLDL uptake, but blockage of LOX-1 did not. Furthermore, high-glucose (15 mmol/L or 30 mmol/L) treatment increased CD86 and CD83 in DCs. High glucose also increased IL-6 and IL-12 secretion and decreased IL-10 secretion.
  
  
  CONCLUSIONS
  High glucose can increase the expression of the scavenger receptors SR-A, CD36 and LOX-1, which can increase the oxLDL-uptake capacity of DCs. High glucose induces a proinflammatory cytokine profile in human DCs, leading to DC maturation. These results support the hypothesis that atherosclerosis is aggravated by hyperglycaemia-induced DC activation and oxLDL uptake.
authors.forename: Hao
authors.initials: H
authors.lastname: Lu
authors.forename: Kang
authors.initials: K
authors.lastname: Yao
authors.forename: Dong
authors.initials: D
authors.lastname: Huang
authors.forename: Aijun
authors.initials: A
authors.lastname: Sun
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.forename: Juying
authors.initials: J
authors.lastname: Qian
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051116:Receptors, Scavenger / Q000235:genetics / Q000378:metabolism*; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D018955:CD36 Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose