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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
(2005) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200405-644st · Cited by 5,932
NOX enzymes and the biology of reactive oxygen
Lambeth, J. D. (2004) · Nature Reviews Immunology · doi:10.1038/nri1312 · Cited by 3,125
Neutrophils and immunity: challenges and opportunities
Nathan, C. (2006) · Nature reviews. Immunology · doi:10.1038/nri1785 · Cited by 2,971
System, A. R. F. T. N. (2003) · American Journal of Infection Control · doi:10.1016/j.ajic.2003.09.002 · Cited by 2,923
Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1
Abo, A., Pick, E., Hall, A., Totty, N. F., Teahan, C. G., & Segal, A. W. (1991) · Nature · doi:10.1038/353668a0 · Cited by 954
Pollock, J. D., Williams, D. A., Gifford, M. A. C., Li, L. L., Du, X., Fisherman, J., Orkin, S. H., Doerschuk, C. M., & Dinauer, M. C. (1995) · Nature Genetics · doi:10.1038/ng0295-202 · Cited by 921
(1999) · American Journal of Infection Control · doi:10.1016/s0196-6553(99)70031-3 · Cited by 899
Regulation of Phagocyte Oxygen Radical Production by the GTP-Binding Protein Rac 2
Knaus, U. G., Heyworth, P. G., Evans, T., Curnutte, J. T., & Bokoch, G. (1991) · Science · doi:10.1126/science.1660188 · Cited by 673
The PX domains of p47phox and p40phox bind to lipid products of PI(3)K
Kanai, F., Liu, H., Field, S. J., Akbary, H., Matsuo, T., Brown, G. E., Cantley, L. C., & Yaffe, M. B. (2001) · Nature Cell Biology · doi:10.1038/35083070 · Cited by 611
Nathan, C., Srimal, S., Farber, C., Sánchez, E., Kabbash, L. G., Asch, A., Gailit, J. O., & Wright, S. D. (1989) · The Journal of Cell Biology · doi:10.1083/jcb.109.3.1341 · Cited by 556
Roberts, A. W., Kim, C., Zhen, L., Lowe, J. B., Kapur, R., Petryniak, B., Spaetti, A., Pollock, J. D., Borneo, J. B., Bradford, G. B., et al. (1999) · Immunity · doi:10.1016/s1074-7613(00)80019-9 · Cited by 556
Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation
Ambruso, D. R., Knall, C., Abell, A. N., Panepinto, J. A., Kurkchubasche, A. G., Thurman, G. W., Gonzalez-Aller, C., Hiester, A. A., deBoer, M., Harbeck, R. J., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.080074897 · Cited by 480
Phospholipase Cγ2 Is Essential in the Functions of B Cell and Several Fc Receptors
Wang, D., Feng, J., Wen, R., Marine, J.-C., Sangster, M. Y., Parganas, E., Hoffmeyer, A., Jackson, C. W., Cleveland, J. L., Murray, P. J., et al. (2000) · Immunity · doi:10.1016/s1074-7613(00)00005-4 · Cited by 475
Syk is required for integrin signaling in neutrophils
Mócsai, A., Zhou, M., Meng, F., Tybulewicz, V. L., & Lowell, C. A. (2002) · Immunity · doi:10.1016/s1074-7613(02)00303-5 · Cited by 421
Eggimann, P., & Pittet, D. (2001) · CHEST Journal · doi:10.1378/chest.120.6.2059 · Cited by 399
NADPH oxidases: not just for leukocytes anymore!
Bokoch, G., & Knaus, U. G. (2003) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(03)00194-4 · Cited by 386
Mócsai, A., Abram, C. L., Jakus, Z., Hu, Y., Lanier, L. L., & Lowell, C. A. (2006) · Nature Immunology · doi:10.1038/ni1407 · Cited by 376
Lowell, C. A., Fumagalli, L., & Berton, G. (1996) · The Journal of Cell Biology · doi:10.1083/jcb.133.4.895 · Cited by 349
Williams, D., Tao, W., Yang, F., Kim, C., Gu, Y., Mansfield, P. J., Levine, J. E., Petryniak, B., Derrow, C. W., Harris, C., et al. (2000) · PubMed · Cited by 333
Molecular composition and regulation of the Nox family NAD(P)H oxidases
Sumimoto, H., Miyano, K., & Takeya, R. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.08.210 · Cited by 306
Regulation of innate immunity by Rho GTPases
Bokoch, G. (2005) · Trends in Cell Biology · doi:10.1016/j.tcb.2005.01.002 · Cited by 295
SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond
Koretzky, G. A., Abtahian, F., & Silverman, M. A. (2006) · Nature reviews. Immunology · doi:10.1038/nri1750 · Cited by 292
Nathan, C. F. (1989) · Blood · doi:10.1182/blood.v73.1.301.bloodjournal731301 · Cited by 266
Fujikawa, K., Miletic, A. V., Alt, F. W., Faccio, R., Brown, T., Hoog, J., Fredericks, J., Nishi, S., Mildiner, S., Moores, S. L., et al. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20030874 · Cited by 228
Self-citationAdhesion-Dependent Degranulation of Neutrophils Requires the Src Family Kinases Fgr and Hck
Mócsai, A., Ligeti, E., Lowell, C. A., & Berton, G. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.2.1120 · Cited by 227
Vav GEFs are required for β2 integrin-dependent functions of neutrophils
Gakidis, M. A. M., Culleré, X., Olson, T. S., Wilsbacher, J. L., Zhang, B., Moores, S. L., Ley, K. F., Swat, W., Mayadas, T. N., & Brugge, J. S. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200404166 · Cited by 222
Self-citationReynolds, L. F., Smyth, L. A., Norton, T., Freshney, N. W., Downward, J., Kioussis, D., & Tybulewicz, V. L. J. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20011663 · Cited by 217
Kim, C., & Dinauer, M. C. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.2.1223 · Cited by 207
Long-term follow-up and outcome of 39 patients with chronic granulomatous disease
Liese, J. G., Kloos, S., Jendrossek, V., Petropoulou, T., Wintergerst, U., Notheis, G., Gahr, M. L., & Belohradsky, B. H. (2000) · The Journal of Pediatrics · doi:10.1067/mpd.2000.109112 · Cited by 195
Nathan, C. F. (1989) · Blood · doi:10.1182/blood.v73.1.301.301 · Cited by 189
Ellson, C. D., Davidson, K., Ferguson, G., O'Connor, R. P., Stephens, L., & Hawkins, P. T. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20052069 · Cited by 186
P-Rex1 Regulates Neutrophil Function
Welch, H. C. E., Condliffe, A. M., Milne, L., Ferguson, G. J., Hill, K., Webb, L. M. C., Okkenhaug, K., Coadwell, W. J., Andrews, S., Thelen, M., et al. (2005) · Current Biology · doi:10.1016/j.cub.2005.09.050 · Cited by 166
Li, S., 山内, 明., Marchal, C. C., Molitoris, J. K., Quilliam, L. A., & Dinauer, M. C. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.9.5043 · Cited by 150
山内, 明., Kim, C., Li, S., Marchal, C. C., Towe, J., Atkinson, S. J., & Dinauer, M. C. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.10.5971 · Cited by 137
P-Rex1 Is a Primary Rac2 Guanine Nucleotide Exchange Factor in Mouse Neutrophils
Dong, X., Mo, Z., Bokoch, G., Guo, C., Li, Z., & Wu, D. (2005) · Current Biology · doi:10.1016/j.cub.2005.09.014 · Cited by 135
Zhang, H., Schaff, U. Y., Green, C. E., Chen, H., Sarantos, M. R., Hu, Y., Wara, D. W., Simon, S. I., & Lowell, C. A. (2006) · Immunity · doi:10.1016/j.immuni.2006.06.014 · Cited by 131
The Expanding Role for ITAM-Based Signaling Pathways in Immune Cells
Abram, C. L., & Lowell, C. A. (2007) · Science s STKE · doi:10.1126/stke.3772007re2 · Cited by 124
p47 phox Deficiency Impairs NF-κB Activation and Host Defense in Pseudomonas Pneumonia
Sadikot, R. T., Zeng, H., Yull, F. E., Li, B., Cheng, D., Kernodle, D. S., Jansen, D., Contag, C. H., Segal, B. H., Holland, S. M., et al. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.3.1801 · Cited by 108
[Chronic granulomatous disease].
Ck, F., Pasternak, J., & Carvalho Ade, A. (1973) · PubMed · Cited by 107
Role for Plastin in Host Defense Distinguishes Integrin Signaling from Cell Adhesion and Spreading
Chen, H., Mócsai, A., Zhang, H., Ding, R., Morisaki, J. H., White, M. J. V., Rothfork, J. M., Heiser, P. W., Colucci‐Guyon, E., Lowell, C. A., et al. (2003) · Immunity · doi:10.1016/s1074-7613(03)00172-9 · Cited by 101
Utomo, A. R. H., Culleré, X., Glogauer, M., Swat, W., & Mayadas, T. N. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.9.6388 · Cited by 90
Self-citationVav proteins control MyD88-dependent oxidative burst
Miletic, A. V., Graham, D. B., Montgrain, V., Fujikawa, K., Kloeppel, T., Brim, K. L., Weaver, B., Schreiber, R. D., Xavier, R. J., & Swat, W. (2006) · Blood · doi:10.1182/blood-2006-07-033662 · Cited by 88
Self-citationChronic Granulomatous Disease; fundamental stages in our understanding of CGD
Assari, T. (2006) · Medical Immunology · doi:10.1186/1476-9433-5-4 · Cited by 87
SLP-76 Regulates Fcγ Receptor and Integrin Signaling in Neutrophils
Newbrough, S., Mócsai, A., Clemens, R., Wu, J. N., Silverman, M. A., Singer, A. L., Lowell, C., & Koretzky, G. (2003) · Immunity · doi:10.1016/s1074-7613(03)00305-4 · Cited by 81
Kim, C., Marchal, C. C., Penninger, J. M., & Dinauer, M. C. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.8.4425 · Cited by 81
Gene therapy for chronic granulomatous disease
Barese, C. N., Goebel, W. S., & Dinauer, M. C. (2004) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.4.9.1423 · Cited by 74
Nosocomial Infections Surveillance
Brachman, P. S. (1993) · Infection Control and Hospital Epidemiology · doi:10.1086/646714 · Cited by 70
Ming, W., Li, S., Billadeau, D. D., Quilliam, L. A., & Dinauer, M. C. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00985-06 · Cited by 61
Carstanjen, D., 山内, 明., Koornneef, A., Zang, H., Filippi, M., Harris, C. E., Towe, J., Atkinson, S. J., Zheng, Y., Dinauer, M. C., et al. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.8.4613 · Cited by 61
Gene therapy for chronic granulomatous disease
Kume, A., & Dinauer, M. C. (2000) · Journal of Laboratory and Clinical Medicine · doi:10.1067/mlc.2000.104458 · Cited by 52
Kim, C., & Dinauer, M. C. (2005) · Journal of Leukocyte Biology · doi:10.1189/jlb.0705371 · Cited by 49
PRAM-1 Is Required for Optimal Integrin-Dependent Neutrophil Function
Clemens, R. A., Newbrough, S. A., Chung, E. Y., Gheith, S. M. F., Singer, A. L., Koretzky, G. A., & Peterson, E. J. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.24.10923-10932.2004 · Cited by 29
Clemens, R. A., Lenox, L. E., Kambayashi, T., Bezman, N., Maltzman, J. S., Nichols, K. E., & Koretzky, G. A. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.7.4606 · Cited by 24
Kimura, K., Miyazaki, S., Tateda, K., Matsumoto, T., TSUJIMOTO, S., & Yamaguchi, K. (1999) · Journal of Medical Microbiology · doi:10.1099/00222615-48-11-1005 · Cited by 16
Synergistic activation of PKD by the B cell antigen receptor and CD19 requires PI3K, Vav1 and PLCγ
Vigorito, E., Kövesdi, D., & Turner, M. (2005) · Cellular Signalling · doi:10.1016/j.cellsig.2005.11.008 · Cited by 13
Antigen receptor signaling: the Tuscan chronicles
Baldari, C. T., Koretzky, G. A., Telford, J. L., & Acuto, O. (2004) · Nature Immunology · doi:10.1038/ni0105-3 · Cited by 4
Research works printed but not linked: 1
- Williams, 2000, Blood., 96, 1646
Cited by
Sorted by citations
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
