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

Abstract

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.

• Authors: Naoko Ozaki, Shinobu Suzuki, Masato Ishida, Yasuyo Harada, Kohji Tanaka, Yayoi Sato, Takeshi Kono, Masato Kubo, Daisuke Kitamura, Jeffrey Encinas, Hiromitsu Hara, Hiroki Yoshida
• Journal: International immunology (Int Immunol) Vol. 24 Issue 9 Pg. 539-50 (Sep 2012) ISSN: 1460-2377 [Electronic] England
• PMID: 22914861 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Cytokines
• Intracellular Signaling Peptides and Proteins
• Receptors, IgG
• Collagen
• Protein-Tyrosine Kinases
• SYK protein, human
• Syk Kinase
• Syk protein, mouse

Topics

• Animals
• Arthritis, Experimental (immunology)
• Autoantibodies (immunology, metabolism)
• Cell Movement (genetics, immunology)
• Cells, Cultured
• Collagen (immunology)
• Cytokines (genetics, metabolism)
• Gene Expression Regulation
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Macrophages (drug effects, immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neutrophils (drug effects, immunology)
• Phagocytosis
• Protein-Tyrosine Kinases (genetics, metabolism)
• Receptors, IgG (metabolism)
• Signal Transduction (genetics, immunology)
• Syk Kinase