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Cited by 119Cell Adhesion Molecules ResearchNeutrophil, Myeloperoxidase and Oxidative MechanismsRheumatoid Arthritis Research and Therapies

Critical role of phospholipase Cγ2 in integrin and Fc receptor-mediated neutrophil functions and the effector phase of autoimmune arthritis

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Jakus, Zoltán, Simon, Edina, Frommhold, David, Sperandio, Markus, Mócsai, Attila·2009·Journal of Experimental Medicine
DOI 10.1084/jem.20081859PMC PMC2699137
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Abstract

β2 integrins and Fcγ receptors are critically involved in neutrophil activation at the site of inflammation. Both receptor types trigger a receptor-proximal tyrosine phosphorylation cascade through Src family kinases and Syk, but further downstream signaling events are poorly understood. We show that phospholipase C (PLC) γ2 is phosphorylated downstream of Src family kinases and Syk during integrin or Fc receptor-mediated activation of neutrophils. PLCγ2−/− neutrophils are completely defective in β2 integrin or Fcγ receptor-mediated functional responses such as respiratory burst, degranulation, or cell spreading in vitro and show reduced adhesion/spreading in inflamed capillary venules in vivo. However, PLCγ2−/− neutrophils respond normally to various other agonists, including chemokines, bacterial formyl peptides, Toll-like receptor ligands, or proinflammatory cytokines, and migrate normally both in vitro and in vivo. To confirm the in vivo relevance of these observations, the effect of the PLCγ2−/− mutation was tested in the K/B×N serum transfer arthritis model, which is known to require β2 integrins, Fcγ receptors, and neutrophils. PLCγ2 deficiency completely protected mice from clinical signs and histological features of arthritis as well as from arthritis-induced loss of articular function. These results identify PLCγ2 as a critical player of integrin and Fc receptor-mediated neutrophil functions and the neutrophil-mediated effector phase of autoimmune arthritis.

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  • In a K/BxN serum-transfer murine model of RA, Vav/PLCγ2-deficient mice were protected from inflammation and bone erosion.

    “In a K/BxN serum-transfer murine model of RA, Vav/PLCγ2-deficient mice were protected from inflammation and bone erosion (73, 112).”

    From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [73]

    The Results (Fig. 7; page unavailable) show that PLCγ2-deficient mice were protected from clinical arthritis and periarticular leukocyte infiltration after K/B×N serum transfer. The cited paper does not establish protection from bone erosion or report a Vav/PLCγ2-deficient genotype. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Previous reports demonstrate involvement of SYK-dependent signalling pathways downstream of integrin in neutrophils and macrophages and a role of PLCγ2 in integrin-mediated neutrophil functions.

    “Previous reports demonstrating the involvement of SYK-dependent signalling pathways downstream of integrin in neutrophils and macrophages32 and specifically the role of PLCγ2 in integrin-mediated neutrophil functions33”

    From PLCγ2 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages (2021) · cites this paper as [33]

  • PLCγ2 is required to facilitate adhesion-dependent neutrophil activation and spreading upon integrin ligation.

    “It was shown that PLCγ2 was required to facilitate adhesion-dependent neutrophil activation and spreading upon integrin ligation33.”

    From PLCγ2 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages (2021) · cites this paper as [33]

  • PLCγ2 is essential in neutrophils for β-2 integrin and FcγR-mediated effects including production of ROS, degranulation, and cell spreading.

    “PLCγ2 is also essential in neutrophils for β-2 integrin and FcγR-mediated effects including production of ROS, degranulation, and cell spreading (73).”

    From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [73]

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Authors
Jakus, Z., Simon, E., Frommhold, D., Sperandio, M., & Mócsai, A.
Affiliations
  • Semmelweis University (HU)
  • Heidelberg University (DE)
  • Institut für Chirurgische Forschung (DE)
Corresponding author
Mócsai, Attila
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2009-03-09
Volume
206
Issue
3
Pages
577-593
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20081859
PMC
PMC2699137
OpenAlex
W2119995150
Cited by
119
References
6
Citations by year
2026: 4 · 2025: 8 · 2023: 11 · 2022: 2 · 2021: 9 · 2020: 6 · 2019: 8 · 2018: 8 · 2017: 3 · 2016: 9 · 2015: 5 · 2014: 8 · 2013: 12 · 2012: 8
FWCI
6.89
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • Wellcome Trust (073976)
  • Fogarty International Center (R03TW006831)
Topics
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Keywords
PLCγ2, neutrophils, beta2 integrins, Fc gamma receptor, autoimmune arthritis, K/BxN serum transfer arthritis, neutrophil activation, respiratory burst, degranulation, cell spreading, neutrophil adhesion, Src family kinases, Syk, receptor tyrosine phosphorylation
MeSH terms
Syk Kinase, Animals, Arthritis, Autoimmune Diseases, Bone Marrow, Cell Membrane, Cell Movement, Chimera, Isoenzymes, Leukocytes, Muscles, N-Formylmethionine Leucyl-Phenylalanine, Neutrophils, Phosphorylation, Protein-Tyrosine Kinases, Signal Transduction, Biomarkers, Receptors, IgG, Receptors, Cytokine, CD18 Antigens, src-Family Kinases, Endothelial Cells, Receptors, G-Protein-Coupled, Intracellular Signaling Peptides and Proteins, Mice, Phospholipase C gamma

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