Critical role of phospholipase Cγ2 in integrin and Fc receptor-mediated neutrophil functions and the effector phase of autoimmune arthritis

Zoltán Jakus, Edina Simon, David Frommhold, Markus Sperandio, Attila Mócsai

Research output: Article

73 Citations (Scopus)

Abstract

β2 integrins and Feγ receptors are critically involved in neutrophil activation at the site of inflammation. Both receptor types trigger a receptor-proximal tyrosine phosphorylation cascade through Src family kinases and Syk, but further downstream signaling events are poorly understood. We show that phospholipase C (PLC) γ2 is phosphorylated downstream of Src family kinases and Syk during integrin or Fc receptor-mediated activation of neutro-phils. PLCγ2-/- neutrophils are completely defective in β2 integrin or Fcy receptor-mediated functional responses such as respiratory burst, degranulation, or cell spreading in vitro and show reduced adhesion/spreading in inflamed capillary venules in vivo. However, PLCγ2-/- neutrophils respond normally to various other agonists, including chemokines, bacterial formyl peptides, Toll-like receptor ligands, or proinflammatory cytokines, and migrate normally both in vitro and in vivo. To confirm the in vivo relevance of these observations, the effect of the PLCγ2-/- mutation was tested in the K/BxN serum transfer arthritis model, which is known to require β2 integrins, Fcγ receptors, and neutrophils. PLCγ2 deficiency completely protected mice from clinical signs and histological features of arthritis as well as from arthritis-induced loss of articular function. These results identify PLCγ2 as a critical player of integrin and Fc eceptor-mediated neutrophil functions and the neutrophil-mediated effector phase of autoimmune arthritis.

Original languageEnglish
Pages (from-to)577-593
Number of pages17
JournalJournal of Experimental Medicine
Volume206
Issue number3
DOIs
Publication statusPublished - márc. 16 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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