Ruby F Fernandez-Boyanapalli1, S Courtney Frasch1, Stacey M Thomas1, Kenneth C Malcolm2, Michael Nicks1, Ronald J Harbeck3, Claudia V Jakubzick1, Raphael Nemenoff4, Peter M Henson3, Steven M Holland5, Donna L Bratton6. 1. Department of Pediatrics, National Jewish Health, Denver, Colo. 2. Department of Medicine, National Jewish Health, Denver, Colo. 3. Department of Pediatrics, National Jewish Health, Denver, Colo; Department of Medicine, National Jewish Health, Denver, Colo; Department of Immunology, National Jewish Health, Denver, Colo. 4. Division of Renal Diseases and Hypertension, Department of Medicine, University of Denver, Denver, Colo. 5. Laboratories of Clinical Infectious Disease, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. 6. Department of Pediatrics, National Jewish Health, Denver, Colo. Electronic address: brattond@njhealth.org.
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. OBJECTIVES: 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.
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 humanCGD, would enhance phagocyte oxidant production and killing of Staphylococcus aureus, a significant pathogen in patients with this disorder. OBJECTIVES: 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: Ju Huang; Veronica Canadien; Grace Y Lam; Benjamin E Steinberg; Mary C Dinauer; Marco A O Magalhaes; Michael Glogauer; Sergio Grinstein; John H Brumell Journal: Proc Natl Acad Sci U S A Date: 2009-04-01 Impact factor: 11.205
Authors: Steven M Holland; Donna L Bratton; Ruby F Fernandez-Boyanapalli; Emilia Liana Falcone; Christa S Zerbe; Beatriz E Marciano; S Courtney Frasch; Peter M Henson Journal: J Allergy Clin Immunol Date: 2015-09-18 Impact factor: 10.793
Authors: Tobias Gutting; Christian A Weber; Philip Weidner; Frank Herweck; Sarah Henn; Teresa Friedrich; Shuiping Yin; Julia Kzhyshkowska; Timo Gaiser; Klaus-Peter Janssen; Wolfgang Reindl; Matthias P A Ebert; Elke Burgermeister Journal: Oncoimmunology Date: 2018-02-01 Impact factor: 8.110