title: Role of p85α in neutrophil extra- and intracellular reactive oxygen species generation.
abstract: Drug resistance is a growing problem that necessitates new strategies to combat pathogens. Neutrophil phagocytosis and production of intracellular ROS, in particular, has been shown to cooperate with antibiotics in the killing of microbes. This study tested the hypothesis that p85α, the regulatory subunit of PI3K, regulates production of intracellular ROS. Genetic knockout of p85α in mice caused decreased expression of catalytic subunits p110α, p110β, and p110δ, but did not change expression levels of the NADPH oxidase complex subunits p67phox, p47phox, and p40phox. When p85α, p55α, and p50α (all encoded by Pik3r1) were deleted, there was an increase in intracellular ROS with no change in phagocytosis in response to both Fcγ receptor and complement receptor stimulation. Furthermore, the increased intracellular ROS correlated with significantly improved neutrophil killing of both methicillin-susceptible and methicillin-resistant S. aureus. Our findings suggest inhibition of p85α as novel approach to improving the clearance of resistant pathogens.
authors.affiliation: Department of Pediatrics, Indianapolis, IN, USA.|Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA.
authors.forename: Xing Jun
authors.initials: XJ
authors.lastname: Li
authors.affiliation: Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA.|Department of Medical & Molecular Genetics, Indianapolis, IN, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Microbiology & Immunology, Indianapolis, IN, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Brandt
authors.affiliation: Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA.|Department of Medical & Molecular Genetics, Indianapolis, IN, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Goodwin
authors.affiliation: Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Peilin
authors.initials: P
authors.lastname: Ma
authors.affiliation: Department of Pediatrics, Indianapolis, IN, USA.|Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA.
authors.forename: Zhenyun
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Indianapolis, IN, USA.|Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA.
authors.forename: Raghu S
authors.initials: RS
authors.lastname: Mali
authors.affiliation: Department of Biostatistics, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA.
authors.forename: Ziyue
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Indianapolis, IN, USA.|Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA.|Department of Medical & Molecular Genetics, Indianapolis, IN, USA.|Department of Microbiology & Immunology, Indianapolis, IN, USA.
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.affiliation: Department of Microbiology & Immunology, Indianapolis, IN, USA.
authors.forename: C Henrique
authors.initials: CH
authors.lastname: Serezani
authors.affiliation: Department of Pediatrics, Indianapolis, IN, USA.|Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA.|Department of Medical & Molecular Genetics, Indianapolis, IN, USA.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Chan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017382:Reactive Oxygen Species; D058543:Class Ia Phosphatidylinositol 3-Kinase; C000622001:Pik3r1 protein, mouse
keywords: Immune response; Immunity; Immunology and Microbiology Section; MRSA; NADPH oxidase; PI3K; neutrophil; p85α