Mac-1 Signaling via Src-Family and Syk Kinases Results in Elastase-Dependent Thrombohemorrhagic Vasculopathy

Junichi Hirahashi, Divya Mekala, Jessica Van Ziffle, Ling Xiao, Simin Saffaripour, Denisa D. Wagner, Steven D. Shapiro, Clifford Lowell, Tanya N. Mayadas

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

CD18 integrins promote neutrophil recruitment, and their engagement activates tyrosine kinases, leading to neutrophil activation. However, the significance of integrin-dependent leukocyte activation in vivo has been difficult to prove. Here, in a model of thrombohemorrhagic vasculitis, the CD18 integrin Mac-1 on neutrophils recognized complement C3 deposited within vessel walls and triggered a signaling pathway involving the Src-family kinase Hck and the Syk tyrosine kinase. This led to neutrophil elastase release, causing hemorrhage, fibrin deposition, and thrombosis. Mice genetically deficient in any of these components (C3, Mac-1, Hck, Syk, or elastase) were resistant to disease despite normal tissue neutrophil accumulation. Disease was restored in Mac-1-deficient mice infused with wild-type, but not kinase- or elastase-deficient, neutrophils. Elastase release in the inflamed tissue was reduced in Mac-1-deficient mice, and a deficiency of Mac-1 or the kinases blocked neutrophil elastase release in vitro. These data suggest that Mac-1 engagement of complement activates tyrosine kinases to promote elastase-dependent blood vessel injury in vivo.

Original languageEnglish
Pages (from-to)271-283
Number of pages13
JournalImmunity
Volume25
Issue number2
DOIs
Publication statusPublished - 2006 Aug 1
Externally publishedYes

Keywords

  • HUMDISEASE
  • MOLIMMUNO
  • SIGNALING

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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