title: Vav/Phospholipase Cgamma2-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 beta2 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 Cgamma2 (PLCgamma2), 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 PLCgamma2(-/-) 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 PLCgamma2(-/-) mice were protected from inflammation and bone erosion in the K/BxN serum-transfer model of arthritis. Mechanistically, Vav and PLCgamma2 control neutrophils mediated spreading and degranulation on integrin-dependent substrates. Consequently, the Vav/PLCgamma2 axis, acting downstream of the integrin receptor, modulated the activation of Pyk-2, Src, and ERK.
  
  
  CONCLUSIONS
  Our findings show that Vav cooperates with PLCgamma2 in modulating neutrophil activation downstream of the integrin receptor. This study identifies a Vav/PLCgamma2-dependent signaling pathway as a possible therapeutic target for the treatment of inflammation and bone disruption in arthritis.
authors.affiliation: Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Viviana
authors.initials: V
authors.lastname: Cremasco
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Graham
authors.forename: Deborah V
authors.initials: DV
authors.lastname: Novack
authors.forename: Wojciech
authors.initials: W
authors.lastname: Swat
authors.forename: Roberta
authors.initials: R
authors.lastname: Faccio