Neutrophil-mediated oxidative burst and host defense are controlled by a Vav-PLCgamma2 signaling axis in mice.
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.
Graham
Daniel B
DB
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Robertson
Charles M
CM
Bautista
Jhoanne
J
Mascarenhas
Francesca
F
Diacovo
M Julia
MJ
Montgrain
Vivianne
V
Lam
Siu Kit
SK
Cremasco
Viviana
V
Dunne
W Michael
WM
Faccio
Roberta
R
Coopersmith
Craig M
CM
Swat
Wojciech
W
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
D004075:Diglycerides; D021122:Protein Subunits; D051567:Proto-Oncogene Proteins c-vav; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D051966:Phospholipase C gamma; D002118:Calcium