REVIEW NADPH oxidase activation in neutrophils: Role of the phosphorylation of its subunits Sahra A. Belambri 1,2 | Lo € ıc Rolas 1 | Houssam Raad 1 | Margarita Hurtado-Nedelec 1,3 | Pham My-Chan Dang 1, * | Jamel El-Benna 1, * 1 Centre de Recherche sur l’Inflammation (CRI), INSERM-U1149, CNRS- ERL8252, Laboratoire d’Excellence Inflamex, Universit  e Paris Diderot- Sorbonne Paris Cit e, Facult  e de M edecine, Site Xavier Bichat, Paris, France 2 Laboratoire de Biochimie Appliqu ee,  Equipe de Recherche: Stress Oxydatif et Inflammation, D epartement de Biochimie, Facult e des Sciences De la Nature et de la Vie, Universit  e Ferhat Abbes 1, S etif, Alg erie 3 D epartement d’Immunologie et d’H ematologie, UF Dysfonctionnements Immunitaires, HUPNVS, H^ opital Bichat, Paris, France Correspondence Jamel El-Benna and Pham My-Chan Dang, Laboratoire d’Excellence Inflamex, Facult e de M edecine, Centre de Recherche sur l’Inflammation (CRI), INSERM- U1149, CNRS-ERL8252, Universit e Paris Diderot-Sorbonne Paris Cit e, Paris, France. Emails: Jamel.elbenna@inserm.fr and my-chan.dang@inserm.fr Funding information Universit  e Paris7 Denis Diderot; Centre National de la Recherche Scientifique; Labex Inflamex; Institut National de la Sant  e et de la Recherche M edicale; VLM Abstract Neutrophils are key cells of innate immunity and during inflammation. Upon acti- vation, they produce large amounts of superoxide anion (O 2 À. ) and ensuing reac- tive oxygen species (ROS) to kill phagocytized microbes. The enzyme responsible for O 2 À. production is called the phagocyte NADPH oxidase. This is a multicom- ponent enzyme system that becomes active after assembly of four cytosolic pro- teins (p47 phox , p67 phox , p40 phox and Rac2) with the transmembrane proteins (p22 phox and gp91 phox , which form the cytochrome b 558 ). gp91 phox represents the catalytic subunit of the NADPH oxidase and is also called NOX2. NADPH oxi- dase-derived ROS are essential for microbial killing and innate immunity; how- ever, excessive ROS production induces tissue injury and prolonged inflammatory reactions that contribute to inflammatory diseases. Thus, NADPH oxidase activa- tion must be tightly regulated in time and space to limit ROS production. NADPH oxidase activation is regulated by several processes such as phosphorylation of its components, exchange of GDP/GTP on Rac2 and binding of p47 phox and p40 phox to phospholipids. This review aims to provide new insights into the role of the phosphorylation of the NADPH oxidase components, that is gp91 phox , p22 phox , p47 phox , p67 phox and p40 phox , in the activation of this enzyme. KEYWORDS gp91 phox , NADPH oxidase, neutrophils, NOX2, p22 phox , p47 phox , p67 phox and p40 phox , protein phosphorylation, Rac2 1 | INTRODUCTION Polymorphonuclear neutrophils are the first line of defence against microbes such as bacteria and fungi. 1-3 Phagocyto- sis of such microbes at the infection site triggers the activation of several neutrophil functions, such as the release of proteases, bactericidal peptides and reactive oxy- gen species (ROS). 4-6 ROS production is initiated by the generation of superoxide anion (O 2 À. ) by the phagocyte NADPH oxidase 7,8 (Figure 1). This reaction involves the monovalent reduction in oxy- gen by means of cytosolic NADPH as the electron donor *Contributed equally to this work. Received: 25 January 2018 | Accepted: 8 May 2018 DOI: 10.1111/eci.12951 Eur J Clin Invest. 2018;48(Suppl. 2):e12951. https://doi.org/10.1111/eci.12951 wileyonlinelibrary.com/journal/eci © 2018 Stichting European Society for Clinical Investigation Journal Foundation | 1 of 9