Tyrosine kinase Btk regulates E-selectin–mediated integrin activation and neutrophil recruitment by controlling phospholipase C (PLC) γ2 and PI3Kγ pathways
Open accessAbstract
Selectins mediate leukocyte rolling, trigger β2-integrin activation, and promote leukocyte recruitment into inflamed tissue. E-selectin binding to P-selectin glycoprotein ligand 1 (PSGL-1) leads to activation of an immunoreceptor tyrosine-based activation motif (ITAM)–dependent pathway, which in turn activates the spleen tyrosine kinase (Syk). However, the signaling pathway linking Syk to integrin activation after E-selectin engagement is unknown. To identify the pathway, we used different gene-deficient mice in autoperfused flow chamber, intravital microscopy, peritonitis, and biochemical studies. We report here that the signaling pathway downstream of Syk divides into a phospholipase C (PLC) γ2– and phosphoinositide 3-kinase (PI3K) γ–dependent pathway. The Tec family kinase Bruton tyrosine kinase (Btk) is required for activating both pathways, generating inositol-3,4,5-trisphosphate (IP3), and inducing E-selectin–mediated slow rolling. Inhibition of this signal-transduction pathway diminished Gαi-independent leukocyte adhesion to and transmigration through endothelial cells in inflamed postcapillary venules of the cremaster. Gαi-independent neutrophil recruitment into the inflamed peritoneal cavity was reduced in Btk−/− and Plcg2−/− mice. Our data demonstrate the functional importance of this newly identified signaling pathway mediated by E-selectin engagement.
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PLCγ2 has a role in neutrophil recruitment via Btk in regulating E-selectin-mediated integrin activation, which facilitates leukocyte rolling and infiltration into inflamed tissues, and subsequent PI3Kγ pathways.
“PLCγ2 also has a role in neutrophil recruitment via Btk in regulating E-selectin–mediated integrin activation, which facilitates leukocyte rolling and infiltration into inflamed tissues, and subsequent PI3Kγ pathways (87).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [87]
The Discussion reports that Btk controls E-selectin–mediated slow rolling through PLCγ2- and PI3Kγ-dependent pathways, and that blocking PLCγ2 abolishes leukocyte extravasation and neutrophil recruitment into inflamed tissue. It describes those pathways as branches downstream of Btk, however, not PI3Kγ as a subsequent pathway downstream of PLCγ2. No page numbers are provided in the supplied passages. (LLM, conf=0.88)
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- Authors
- Mueller, H., Stadtmann, A., Van Aken, H., Hirsch, E., Wang, D., Ley, K., & Zarbock, A.
- Affiliations
- Max Planck Society (DE)
- Department of Anesthesiology and Intensive Care Medicine, University of Münster, Münster, Germany;
- University of Turin (IT)
- Versiti Blood Center of Wisconsin (US)
- La Jolla Institute for Immunology (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-04-15
- Volume
- 115
- Issue
- 15
- Pages
- 3118-3127
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2858472
- OpenAlex
- W2102637482
- Cited by
- 164
- References
- 51
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 5 · 2023: 7 · 2022: 8 · 2021: 11 · 2020: 7 · 2019: 9 · 2018: 13 · 2017: 7 · 2016: 11 · 2015: 11 · 2014: 8 · 2013: 14 · 2012: 18
- FWCI
- 11.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medicine
- National Institute of Allergy and Infectious Diseases (R01AI079087)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Keywords
- Bruton's tyrosine kinase, E-selectin, integrin activation, neutrophil recruitment, PLCγ2, PI3Kγ, Syk signaling, leukocyte rolling, leukocyte adhesion, transmigration, inositol trisphosphate, Tec family kinases, peritonitis, cremaster muscle
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Animals, Cell Adhesion, Enzyme Activation, Mice, Inbred C57BL, Neutrophils, Phosphorylation, Protein-Tyrosine Kinases, Signal Transduction, CD18 Antigens, Chemokines, E-Selectin, GTP-Binding Protein alpha Subunits, Gi-Go, Phosphatidylinositol 3-Kinases, Neutrophil Infiltration, Leukocyte Rolling, p38 Mitogen-Activated Protein Kinases, Mice, Phospholipase C gamma
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