A Metabolic Shift toward Pentose Phosphate Pathway Is Necessary for Amyloid Fibril- and Phorbol 12-Myristate 13-Acetate-induced Neutrophil Extracellular Trap (NET) Formation

Neutrophils are the main defense cells of the innate immune system. Upon stimulation, neutrophils release their chromosomal DNA to trap and kill microorganisms and inhibit their dissemination. These chromatin traps are termed neutrophil extracellular traps (NETs) and are decorated with granular and...

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Bibliographic Details
Published in:	The Journal of biological chemistry Vol. 290; no. 36; pp. 22174 - 22183
Main Authors:	Azevedo, Estefania P., Rochael, Natalia C., Guimarães-Costa, Anderson B., de Souza-Vieira, Thiago S., Ganilho, Juliana, Saraiva, Elvira M., Palhano, Fernando L., Foguel, Debora
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 04-09-2015 American Society for Biochemistry and Molecular Biology
Subjects:	amyloid Amyloid - pharmacology Amyloid - ultrastructure Cell Biology Extracellular Traps - drug effects Extracellular Traps - metabolism Fructose - metabolism Fructose - pharmacology Glucose - metabolism Glucose - pharmacology glucose-6-phosphate dehydrogenase (G6PD or G6PDH) Glucosephosphate Dehydrogenase - metabolism Humans Immunohistochemistry Microscopy, Confocal Microscopy, Electron, Transmission NADPH oxidase neutrophil Neutrophils - drug effects Neutrophils - metabolism Pentose Phosphate Pathway pentose phosphate pathway (PPP) Proto-Oncogene Proteins c-akt - metabolism Reactive Oxygen Species - metabolism Tetradecanoylphorbol Acetate - pharmacology pentose phosphate pathway (PPP) amyloid neutrophil glucose-6-phosphate dehydrogenase (G6PD or G6PDH) NADPH oxidase
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Summary:	Neutrophils are the main defense cells of the innate immune system. Upon stimulation, neutrophils release their chromosomal DNA to trap and kill microorganisms and inhibit their dissemination. These chromatin traps are termed neutrophil extracellular traps (NETs) and are decorated with granular and cytoplasm proteins. NET release can be induced by several microorganism membrane components, phorbol 12-myristate 13-acetate as well as by amyloid fibrils, insoluble proteinaceous molecules associated with more than 40 different pathologies among other stimuli. The intracellular signaling involved in NET formation is complex and remains unclear for most tested stimuli. Herein we demonstrate that a metabolic shift toward the pentose phosphate pathway (PPP) is necessary for NET release because glucose-6-phosphate dehydrogenase (G6PD), an important enzyme from PPP, fuels NADPH oxidase with NADPH to produce superoxide and thus induce NETs. In addition, we observed that mitochondrial reactive oxygen species, which are NADPH-independent, are not effective in producing NETs. These data shed new light on how the PPP and glucose metabolism contributes to NET formation. Background: Neutrophil extracellular traps (NETs) are DNA meshes that snare and kill microorganisms, impeding their dissemination. Results: Glucose but not fructose supports NET formation through a metabolic shift toward pentose phosphate pathway (PPP). Conclusion: PPP impairment leads to decreased NET production. Significance: This study provides novel knowledge about the mechanisms of NET induction, opening new avenues of study and intervention.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Both authors contributed equally to this work.
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M115.640094