Vav/Phospholipase Cγ2–mediated control of a neutrophil‐dependent murine model of rheumatoid arthritis

Abstract

Objective Accumulating evidence indicates an important role of neutrophils in the development of rheumatoid arthritis (RA). Recruitment of neutrophils to the joint space and release of proteolytic enzymes can exacerbate tissue damage and the inflammatory response related to RA. Engagement of β2 integrin and subsequent activation of downstream signaling have been shown to be fundamental for activation of neutrophil effector functions. The aim of this study was to test the hypothesis that Vav and phospholipase Cγ2 (PLCγ2), two molecules involved in integrin signaling, are required for arthritis generation and neutrophil activation in a mouse model of arthritis. Methods Arthritis was induced in wild‐type (WT), Vav^null, and PLCγ2^−/− mice using the K/BxN serum–transfer model. Neutrophil function was assessed by analyses of adhesion, spreading, and degranulation on integrin‐dependent substrates. Regulation of integrin signaling was determined by analyzing the phosphorylation of Pyk‐2, Src, and ERK. Results Vav^null and PLCγ2^−/− mice were protected from inflammation and bone erosion in the K/BxN serum–transfer model of arthritis. Mechanistically, Vav and PLCγ2 control neutrophils mediated spreading and degranulation on integrin‐dependent substrates. Consequently, the Vav/PLCγ2 axis, acting downstream of the integrin receptor, modulated the activation of Pyk‐2, Src, and ERK. Conclusion Our findings show that Vav cooperates with PLCγ2 in modulating neutrophil activation downstream of the integrin receptor. This study identifies a Vav/PLCγ2‐dependent signaling pathway as a possible therapeutic target for the treatment of inflammation and bone disruption in arthritis.