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Research ArticleImmunology Free access | 10.1172/JCI32729

Neutrophil-mediated oxidative burst and host defense are controlled by a Vav-PLCγ2 signaling axis in mice

Daniel B. Graham,1 Charles M. Robertson,2 Jhoanne Bautista,1 Francesca Mascarenhas,1 M. Julia Diacovo,1 Vivianne Montgrain,1 Siu Kit Lam,1 Viviana Cremasco,3 W. Michael Dunne,1 Roberta Faccio,3 Craig M. Coopersmith,2,4 and Wojciech Swat1

1Department of Pathology and Immunology, 2Department of Surgery, 3Department of Orthopedic Surgery and Department of Cell Biology and Physiology, and 4Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.

Address correspondence to: Wojciech Swat, Washington University School of Medicine, Box 8118, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA. Phone: (314) 747-8889; Fax: (314) 362-4096; E-mail: swat@wustl.edu.

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1Department of Pathology and Immunology, 2Department of Surgery, 3Department of Orthopedic Surgery and Department of Cell Biology and Physiology, and 4Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.

Address correspondence to: Wojciech Swat, Washington University School of Medicine, Box 8118, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA. Phone: (314) 747-8889; Fax: (314) 362-4096; E-mail: swat@wustl.edu.

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1Department of Pathology and Immunology, 2Department of Surgery, 3Department of Orthopedic Surgery and Department of Cell Biology and Physiology, and 4Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.

Address correspondence to: Wojciech Swat, Washington University School of Medicine, Box 8118, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA. Phone: (314) 747-8889; Fax: (314) 362-4096; E-mail: swat@wustl.edu.

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1Department of Pathology and Immunology, 2Department of Surgery, 3Department of Orthopedic Surgery and Department of Cell Biology and Physiology, and 4Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.

Address correspondence to: Wojciech Swat, Washington University School of Medicine, Box 8118, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA. Phone: (314) 747-8889; Fax: (314) 362-4096; E-mail: swat@wustl.edu.

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1Department of Pathology and Immunology, 2Department of Surgery, 3Department of Orthopedic Surgery and Department of Cell Biology and Physiology, and 4Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.

Address correspondence to: Wojciech Swat, Washington University School of Medicine, Box 8118, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA. Phone: (314) 747-8889; Fax: (314) 362-4096; E-mail: swat@wustl.edu.

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1Department of Pathology and Immunology, 2Department of Surgery, 3Department of Orthopedic Surgery and Department of Cell Biology and Physiology, and 4Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.

Address correspondence to: Wojciech Swat, Washington University School of Medicine, Box 8118, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA. Phone: (314) 747-8889; Fax: (314) 362-4096; E-mail: swat@wustl.edu.

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1Department of Pathology and Immunology, 2Department of Surgery, 3Department of Orthopedic Surgery and Department of Cell Biology and Physiology, and 4Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.

Address correspondence to: Wojciech Swat, Washington University School of Medicine, Box 8118, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA. Phone: (314) 747-8889; Fax: (314) 362-4096; E-mail: swat@wustl.edu.

Find articles by Lam, S. in: PubMed | Google Scholar

1Department of Pathology and Immunology, 2Department of Surgery, 3Department of Orthopedic Surgery and Department of Cell Biology and Physiology, and 4Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.

Address correspondence to: Wojciech Swat, Washington University School of Medicine, Box 8118, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA. Phone: (314) 747-8889; Fax: (314) 362-4096; E-mail: swat@wustl.edu.

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1Department of Pathology and Immunology, 2Department of Surgery, 3Department of Orthopedic Surgery and Department of Cell Biology and Physiology, and 4Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.

Address correspondence to: Wojciech Swat, Washington University School of Medicine, Box 8118, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA. Phone: (314) 747-8889; Fax: (314) 362-4096; E-mail: swat@wustl.edu.

Find articles by Dunne, W. in: PubMed | Google Scholar

1Department of Pathology and Immunology, 2Department of Surgery, 3Department of Orthopedic Surgery and Department of Cell Biology and Physiology, and 4Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.

Address correspondence to: Wojciech Swat, Washington University School of Medicine, Box 8118, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA. Phone: (314) 747-8889; Fax: (314) 362-4096; E-mail: swat@wustl.edu.

Find articles by Faccio, R. in: PubMed | Google Scholar

1Department of Pathology and Immunology, 2Department of Surgery, 3Department of Orthopedic Surgery and Department of Cell Biology and Physiology, and 4Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.

Address correspondence to: Wojciech Swat, Washington University School of Medicine, Box 8118, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA. Phone: (314) 747-8889; Fax: (314) 362-4096; E-mail: swat@wustl.edu.

Find articles by Coopersmith, C. in: PubMed | Google Scholar

1Department of Pathology and Immunology, 2Department of Surgery, 3Department of Orthopedic Surgery and Department of Cell Biology and Physiology, and 4Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.

Address correspondence to: Wojciech Swat, Washington University School of Medicine, Box 8118, 660 S. Euclid Ave., St. Louis, Missouri 63110, USA. Phone: (314) 747-8889; Fax: (314) 362-4096; E-mail: swat@wustl.edu.

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Published October 11, 2007 - More info

J Clin Invest. https://doi.org/10.1172/JCI32729.
© 2007 The American Society for Clinical Investigation
Published October 11, 2007 - Version history
Received: May 18, 2007; Accepted: July 18, 2007
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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–γ2 (PLC-γ2) 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-γ2 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.

Version history
  • Version 1 (October 11, 2007): No description
  • Version 2 (November 1, 2007): No description
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