Role of p85α in neutrophil extra- and intracellular reactive oxygen species generation

// Xing Jun Li 1,2,* , Lisa Deng 2,3,* , Stephanie L. Brandt 4 , Charles B. Goodwin 2,3 , Peilin Ma 5 , Zhenyun Yang 1,2 , Raghu S. Mali 1,2 , Ziyue Liu 6 , Reuben Kapur 1,2,3,4 , C. Henrique Serezani 4 and Rebecca J. Chan 1,2,3 1 Department of Pediatrics, Indianapolis, IN, USA 2 Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA 3 Department of Medical & Molecular Genetics, Indianapolis, IN, USA 4 Department of Microbiology & Immunology, Indianapolis, IN, USA 5 Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA 6 Department of Biostatistics, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA * These authors have contributed equally to this work Correspondence to: Rebecca J. Chan, email: // Keywords : PI3K, p85α, neutrophil, NADPH oxidase, MRSA, Immunology and Microbiology Section, Immune response, Immunity Received : February 16, 2016 Accepted : March 23, 2016 Published : March 30, 2016 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 p67 phox , p47 phox , and p40 phox . 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.