title: Pioglitazone restores phagocyte mitochondrial oxidants and bactericidal capacity in chronic granulomatous disease.
abstract: BACKGROUND
  Deficient production of reactive oxygen species (ROS) by the phagocyte nicotinamide adenine dinucleotide (NADPH) oxidase in patients with chronic granulomatous disease (CGD) results in susceptibility to certain pathogens secondary to impaired oxidative killing and mobilization of other phagocyte defenses. Peroxisome proliferator-activated receptor (PPAR) γ agonists, including pioglitazone, approved for type 2 diabetes therapy alter cellular metabolism and can heighten ROS production. It was hypothesized that pioglitazone treatment of gp91(phox-/-) mice, a murine model of human CGD, would enhance phagocyte oxidant production and killing of Staphylococcus aureus, a significant pathogen in patients with this disorder.
  
  
  OBJECTIVE
  We sought to determine whether pioglitazone treatment of gp91(phox-/-) mice enhanced phagocyte oxidant production and host defense.
  
  
  METHODS
  Wild-type and gp91(phox-/-) mice were treated with the PPARγ agonist pioglitazone, and phagocyte ROS and killing of S aureus were investigated.
  
  
  RESULTS
  As demonstrated by 3 different ROS-sensing probes, short-term treatment of gp91(phox-/-) mice with pioglitazone enhanced stimulated ROS production in neutrophils and monocytes from blood and neutrophils and inflammatory macrophages recruited to tissues. Mitochondria were identified as the source of ROS. Findings were replicated in human monocytes from patients with CGD after ex vivo pioglitazone treatment. Importantly, although mitochondrial (mt)ROS were deficient in gp91(phox-/-) phagocytes, their restoration with treatment significantly enabled killing of S aureus both ex vivo and in vivo.
  
  
  CONCLUSIONS
  Together, the data support the hypothesis that signaling from the NADPH oxidase under normal circumstances governs phagocyte mtROS production and that such signaling is lacking in the absence of a functioning phagocyte oxidase. PPARγ agonism appears to bypass the need for the NADPH oxidase for enhanced mtROS production and partially restores host defense in CGD.
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: Ruby F
authors.initials: RF
authors.lastname: Fernandez-Boyanapalli
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: S Courtney
authors.initials: SC
authors.lastname: Frasch
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: Stacey M
authors.initials: SM
authors.lastname: Thomas
authors.affiliation: Department of Medicine, National Jewish Health, Denver, Colo.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Malcolm
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: Michael
authors.initials: M
authors.lastname: Nicks
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo; Department of Medicine, National Jewish Health, Denver, Colo; Department of Immunology, National Jewish Health, Denver, Colo.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Harbeck
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: Claudia V
authors.initials: CV
authors.lastname: Jakubzick
authors.affiliation: Division of Renal Diseases and Hypertension, Department of Medicine, University of Denver, Denver, Colo.
authors.forename: Raphael
authors.initials: R
authors.lastname: Nemenoff
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo; Department of Medicine, National Jewish Health, Denver, Colo; Department of Immunology, National Jewish Health, Denver, Colo.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Henson
authors.affiliation: Laboratories of Clinical Infectious Disease, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo. Electronic address: brattond@njhealth.org.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Bratton
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006105:Granulomatous Disease, Chronic / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D010586:Phagocytes / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D010587:Phagocytosis / Q000276:immunology; D000077205:Pioglitazone; D017382:Reactive Oxygen Species / Q000378:metabolism; D013211:Staphylococcus aureus / Q000276:immunology; D013481:Superoxides / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D008562:Membrane Glycoproteins; D016877:Oxidants; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D013481:Superoxides; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000077205:Pioglitazone
keywords: Chronic granulomatous disease; mitochondria; oxidants; phagocytes; thioglitazones