The Neutrophil Btk Signalosome Regulates Integrin Activation During Sterile Inflammation

Immunity. 2016 Jan 19;44(1):73-87. doi: 10.1016/j.immuni.2015.11.011. Epub 2016 Jan 5.

Abstract

Neutrophils are recruited from the blood to sites of sterile inflammation, where they are involved in wound healing but can also cause tissue damage. During sterile inflammation, necrotic cells release pro-inflammatory molecules including formylated peptides. However, the signaling pathway triggered by formylated peptides to integrin activation and leukocyte recruitment is unknown. By using spinning-disk confocal intravital microscopy, we examined the molecular mechanisms of leukocyte recruitment to sites of focal hepatic necrosis in vivo. We demonstrated that the Bruton's tyrosine kinase (Btk) was required for multiple Mac-1 activation events involved in neutrophil recruitment and functions during sterile inflammation triggered by fMLF. The Src family kinase Hck, Wiskott-Aldrich-syndrome protein, and phospholipase Cγ2 were also involved in this pathway required for fMLF-triggered Mac-1 activation and neutrophil recruitment. Thus, we have identified a neutrophil Btk signalosome that is involved in a signaling pathway triggered by formylated peptides leading to the selective activation of Mac-1 and neutrophil recruitment during sterile inflammation.

Keywords: Btk; Src family kinases; WASp; fMLF; integrin; phospholipase C; signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • Flow Cytometry
  • Inflammation
  • Integrins / immunology
  • Integrins / metabolism*
  • Liver Diseases / immunology
  • Liver Diseases / metabolism
  • Mice
  • Microscopy, Confocal
  • N-Formylmethionine Leucyl-Phenylalanine / immunology
  • Necrosis / immunology
  • Neutrophil Infiltration / immunology*
  • Protein-Tyrosine Kinases / immunology*
  • Protein-Tyrosine Kinases / metabolism
  • Signal Transduction / immunology*

Substances

  • Integrins
  • N-Formylmethionine Leucyl-Phenylalanine
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • Btk protein, mouse