Priming of neutrophil oxidative burst in diabetes requires preassembly of the NADPH oxidase

Hyperglycemia associated with diabetes mellitus results in the priming of neutrophils leading to oxidative stress that is, in part, responsible for diabetic complications. p47phox, a NADPH oxidase cytosolic subunit, is a key protein in the assembly of the NADPH oxidase leading to superoxide generati...

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Published in:Journal of leukocyte biology 2008-07, Vol.84 (1), p.292-301
Main Authors: Omori, Kazuhiro, Ohira, Taisuke, Uchida, Yushi, Ayilavarapu, Srinivas, Batista, Eraldo L., Yagi, Motohiko, Iwata, Tomoyuki, Liu, Hongsheng, Hasturk, Hatice, Kantarci, Alpdogan, Van Dyke, Thomas E.
Format: Article
Language:English
Subjects:
Adult
cell activation
Cell Membrane - drug effects
Cell Membrane - enzymology
Diabetes Mellitus - enzymology
Diabetes Mellitus - pathology
Female
Flavonoids - pharmacology
HL-60 Cells
Humans
inflammation
Male
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - metabolism
N-Formylmethionine Leucyl-Phenylalanine - pharmacology
NADPH Oxidases - metabolism
Neutrophils - drug effects
Neutrophils - enzymology
Neutrophils - pathology
Oxidative Stress
p38 Mitogen-Activated Protein Kinases - metabolism
Phosphorylation - drug effects
Protein Transport - drug effects
Receptor for Advanced Glycation End Products
Receptors, Immunologic - metabolism
Receptors, Signal Transduction, and Genes
Respiratory Burst - drug effects
signal transduction
Superoxides - metabolism
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Summary:Hyperglycemia associated with diabetes mellitus results in the priming of neutrophils leading to oxidative stress that is, in part, responsible for diabetic complications. p47phox, a NADPH oxidase cytosolic subunit, is a key protein in the assembly of the NADPH oxidase leading to superoxide generation. Little is known about the priming mechanism of oxidative pathways in neutrophils of people with diabetes. In this study, the kinetics of p47phox activation was investigated by comparing neutrophils from diabetic and healthy subjects, and the mechanism of hyperglycemia‐induced changes was studied by using neutrophil‐like HL‐60 cells as a model. In resting neutrophils from diabetic subjects, p47phox prematurely translocates to the cell membrane and preassembles with p22phox, a NADPH oxidase membrane subunit. This premature p47phox translocation and preassembly with p22phox were also observed in HL‐60 cells cultured with high glucose (HG; 25 mM) and with the specific ligand for the receptor for advanced glycation end products (RAGE), S100B. Phosphorylation of ERK1/2, but not p38 MAPK, was the primary signaling pathway, as evidenced by PD98059 suppressing the translocation of p47phox in HL‐60 cells incubated with HG and S100B. HL‐60 cells cultured in HG and S100B exhibited a 1.8‐fold increase in fMLP‐induced superoxide generation compared with those cultured in normal glucose (5.5 mM). These data suggest that HG and increased AGE prime neutrophils and increase oxidative stress inducing the translocation of p47phox to the cell membrane and preassembly with p22phox by stimulating a RAGE‐ERK1/2 pathway.
ISSN:0741-5400
1938-3673
DOI:10.1189/jlb.1207832