title: A Metabolic Shift toward Pentose Phosphate Pathway Is Necessary for Amyloid Fibril- and Phorbol 12-Myristate 13-Acetate-induced Neutrophil Extracellular Trap (NET) Formation.
abstract: 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.
authors.affiliation: From the Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Estrutural, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902 and.
authors.forename: Estefania P
authors.initials: EP
authors.lastname: Azevedo
authors.affiliation: Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-970, Brazil.
authors.forename: Natalia C
authors.initials: NC
authors.lastname: Rochael
authors.affiliation: Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-970, Brazil.
authors.forename: Anderson B
authors.initials: AB
authors.lastname: Guimarães-Costa
authors.affiliation: Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-970, Brazil.
authors.forename: Thiago S
authors.initials: TS
authors.lastname: de Souza-Vieira
authors.affiliation: From the Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Estrutural, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902 and.
authors.forename: Juliana
authors.initials: J
authors.lastname: Ganilho
authors.affiliation: Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-970, Brazil esaraiva@micro.ufrj.br.
authors.forename: Elvira M
authors.initials: EM
authors.lastname: Saraiva
authors.affiliation: From the Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Estrutural, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902 and palhano@bioqmed.ufrj.br.
authors.forename: Fernando L
authors.initials: FL
authors.lastname: Palhano
authors.affiliation: From the Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Estrutural, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902 and foguel@bioqmed.ufrj.br.
authors.forename: Debora
authors.initials: D
authors.lastname: Foguel
mesh_terms: D000682:Amyloid / Q000494:pharmacology* / Q000648:ultrastructure; D065206:Extracellular Traps / Q000187:drug effects* / Q000378:metabolism; D005632:Fructose / Q000378:metabolism / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010427:Pentose Phosphate Pathway; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
chemical_list: D000682:Amyloid; D017382:Reactive Oxygen Species; D005632:Fructose; D005954:Glucosephosphate Dehydrogenase; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate
keywords: NADPH oxidase; amyloid; glucose-6-phosphate dehydrogenase (G6PD or G6PDH); neutrophil; pentose phosphate pathway (PPP)