The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.
Neutrophil-mediated oxidative burst and host defense are controlled by a Vav-PLCγ2 signaling axis in mice
Open accessAbstract
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.
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“In addition to FcR signaling requiring PLCγ2 for efficient ROS production in murine neutrophils, PLCγ2 is also essential for postintegrin signaling induction of ROS, as well as being critical for the neutrophil-dependent host defense against bacterial infections in vivo (80).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [80]
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Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1
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Regulation of Phagocyte Oxygen Radical Production by the GTP-Binding Protein Rac 2
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The PX domains of p47phox and p40phox bind to lipid products of PI(3)K
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Neutrophils to the ROScue: Mechanisms of NADPH oxidase activation and bacterial resistance
Nguyen, G. T., Green, E. R., & Mecsas, J. (2017) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2017.00373 · Cited by 741
Neutrophils as emerging therapeutic targets
Németh, T., Sperandio, M., & Mócsai, A. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0054-z · Cited by 676
Neutrophil cell surface receptors and their intracellular signal transduction pathways
Futosi, K., Fodor, S., & Mócsai, A. (2013) · International Immunopharmacology · doi:10.1016/j.intimp.2013.06.034 · Cited by 642
Are Reactive Oxygen Species Always Detrimental to Pathogens?
Paiva, C. N., & Bozza, M. T. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5447 · Cited by 577
The Ins and Outs of Leukocyte Integrin Signaling
Abram, C. L., & Lowell, C. A. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132554 · Cited by 553
Metadata
- Authors
- Graham, D. B., Robertson, C. M., Bautista, J., Mascarenhas, F., Diacovo, M. J., Montgrain, V., Lam, S. K., Cremasco, V., Dunne, W. M., Faccio, R., Coopersmith, C. M., & Swat, W.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Swat, Wojciech
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2007-11-01
- Volume
- 117
- Issue
- 11
- Pages
- 3445-3452
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2000813
- OpenAlex
- W1987998552
- Cited by
- 124
- References
- 55
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 7 · 2021: 8 · 2020: 6 · 2019: 2 · 2018: 4 · 2017: 3 · 2016: 7 · 2015: 5 · 2014: 4 · 2013: 15 · 2012: 10
- FWCI
- 3.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- National Institutes of Health (GM072808)
- National Cancer Institute (T32CA009547)
- National Institute of General Medical Sciences (R01GM072808, GM 072808, GM66202, R01GM066202)
- National Institute of Allergy and Infectious Diseases (AI 063024-02, AI-06107703)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- neutrophil respiratory burst, Vav, PLCγ2, NADPH oxidase, NOX2, integrin signaling, neutrophil adhesion, reactive oxygen species, chronic granulomatous disease, Staphylococcus aureus, Pseudomonas aeruginosa, diacylglycerol, intracellular calcium, host defense, nosocomial pneumonia
- MeSH terms
- Animals, Calcium, Cell Adhesion, Diglycerides, Granulomatous Disease, Chronic, Humans, Neutrophils, Pseudomonas Infections, Staphylococcal Infections, Signal Transduction, Respiratory Burst, Reactive Oxygen Species, Mice, Knockout, Pneumonia, Bacterial, Sepsis, NADPH Oxidases, Protein Subunits, Mice, Proto-Oncogene Proteins c-vav, Phospholipase C gamma
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