Syk-dependent signaling pathways in neutrophils and macrophages are indispensable in the pathogenesis of anti-collagen antibody-induced arthritis

Spleen tyrosine kinase (Syk) is associated with Fcγ receptors (FcγRs) and transmits activation signals through FcγRs in myeloid cells. Thus, application of drugs to inhibit Syk activity can affect the development of immune diseases mediated by autoantibodies, while unexpected systemic effects by the...

Full description

Saved in:
Bibliographic Details
Published in:International immunology 2012-09, Vol.24 (9), p.539-550
Main Authors: Ozaki, Naoko, Suzuki, Shinobu, Ishida, Masato, Harada, Yasuyo, Tanaka, Kohji, Sato, Yayoi, Kono, Takeshi, Kubo, Masato, Kitamura, Daisuke, Encinas, Jeffrey, Hara, Hiromitsu, Yoshida, Hiroki
Format: Article
Language:English
Subjects:
Animals
Arthritis, Experimental - immunology
Autoantibodies - immunology
Autoantibodies - metabolism
Cell Movement - genetics
Cell Movement - immunology
Cells, Cultured
Collagen - immunology
Cytokines - genetics
Cytokines - metabolism
Gene Expression Regulation
Humans
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
Macrophages - drug effects
Macrophages - immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Neutrophils - drug effects
Neutrophils - immunology
Phagocytosis
Protein-Tyrosine Kinases - genetics
Protein-Tyrosine Kinases - metabolism
Receptors, IgG - metabolism
Signal Transduction - genetics
Signal Transduction - immunology
Syk Kinase
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Spleen tyrosine kinase (Syk) is associated with Fcγ receptors (FcγRs) and transmits activation signals through FcγRs in myeloid cells. Thus, application of drugs to inhibit Syk activity can affect the development of immune diseases mediated by autoantibodies, while unexpected systemic effects by the inhibition may be concerned because Syk has multiple physiological functions. We used tamoxifen-inducible systemic conditional Syk knockout (KO) mice to evaluate the role of Syk in the pathogenesis of autoimmune arthritis and to investigate the systemic effects of Syk deletion. In a collagen antibody-induced arthritis model, Syk KO mice were almost completely protected from disease induction and showed significantly attenuated accumulation of neutrophils and macrophages in the joints. Syk-deleted macrophages showed less IL-6 and MCP-1 production upon FcγR ligation and exhibited reduced FcγR-mediated phagocytosis in vitro. Syk-deleted macrophages produce more RANTES upon FcγR ligation, indicating a Syk-independent signaling through the FcγR. We further found that both wild-type and Syk-deleted macrophages induced neutrophil chemotaxis upon FcγR ligation in vitro, and air-pouch model demonstrated that Syk-deleted neutrophils have a potential to infiltrate into local tissues in response to collagen and anti-collagen antibodies. However, Syk-deleted neutrophils exhibited greatly decreased neutrophil extracellular traps formation and FcγR-mediated phagocytosis. Our results indicated that Syk deficiency rendered mice completely unresponsive to immune activation by anti-collagen antibodies with disabling one pathway of FcγR-mediated signaling that was crucial for arthritis induction.
ISSN:0953-8178
1460-2377
DOI:10.1093/intimm/dxs078