title: Neutrophil-mediated oxidative burst and host defense are controlled by a Vav-PLCgamma2 signaling axis in mice.
abstract: Oxidative burst, a critical antimicrobial mechanism of neutrophils, involves the rapid generation and release of reactive oxygen intermediates (ROIs) by the NADPH oxidase complex. Genetic mutations in an NADPH oxidase subunit, gp91 (also referred to as NOX2), are associated with chronic granulomatous disease (CGD), which is characterized by recurrent and life-threatening microbial infections. To combat such infections, ROIs are produced by neutrophils after stimulation by integrin-dependent adhesion to the ECM in conjunction with stimulation from inflammatory mediators, or microbial components containing pathogen-associated molecular patterns. In this report, we provide genetic evidence that both the Vav family of Rho GTPase guanine nucleotide exchange factors (GEFs) and phospholipase C-gamma2 (PLC-gamma2) are critical mediators of adhesion-dependent ROI production by neutrophils in mice. We also demonstrated that Vav was critically required for neutrophil-dependent host defense against systemic infection by Staphylococcus aureus and Pseudomonas aeruginosa, 2 common pathogens associated with fatal cases of hospital-acquired pneumonia. We identified a molecular pathway in which Vav GEFs linked integrin-mediated signaling with PLC-gamma2 activation, release of intracellular Ca2+ cations, and generation of diacylglycerol to control assembly of the NADPH oxidase complex and ROI production by neutrophils. Taken together, our data indicate that integrin-dependent signals generated during neutrophil adhesion contribute to the activation of NADPH oxidase by a variety of distinct effector pathways, all of which require Vav.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Graham
authors.forename: Charles M
authors.initials: CM
authors.lastname: Robertson
authors.forename: Jhoanne
authors.initials: J
authors.lastname: Bautista
authors.forename: Francesca
authors.initials: F
authors.lastname: Mascarenhas
authors.forename: M Julia
authors.initials: MJ
authors.lastname: Diacovo
authors.forename: Vivianne
authors.initials: V
authors.lastname: Montgrain
authors.forename: Siu Kit
authors.initials: SK
authors.lastname: Lam
authors.forename: Viviana
authors.initials: V
authors.lastname: Cremasco
authors.forename: W Michael
authors.initials: WM
authors.lastname: Dunne
authors.forename: Roberta
authors.initials: R
authors.lastname: Faccio
authors.forename: Craig M
authors.initials: CM
authors.lastname: Coopersmith
authors.forename: Wojciech
authors.initials: W
authors.lastname: Swat
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D004075:Diglycerides / Q000378:metabolism; D006105:Granulomatous Disease, Chronic / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology*; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D018410:Pneumonia, Bacterial / Q000378:metabolism / Q000382:microbiology; D021122:Protein Subunits / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst; D018805:Sepsis / Q000378:metabolism / Q000382:microbiology; D015398:Signal Transduction / Q000502:physiology*; D013203:Staphylococcal Infections / Q000378:metabolism
chemical_list: D004075:Diglycerides; D021122:Protein Subunits; D051567:Proto-Oncogene Proteins c-vav; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D051966:Phospholipase C gamma; D002118:Calcium