Mac-1 signaling via Src-family and Syk kinases results in elastase-dependent thrombohemorrhagic vasculopathy.

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.

• Authors: Junichi Hirahashi, Divya Mekala, Jessica Van Ziffle, Ling Xiao, Simin Saffaripour, Denisa D Wagner, Steven D Shapiro, Clifford Lowell, Tanya N Mayadas
• Journal: Immunity (Immunity) Vol. 25 Issue 2 Pg. 271-83 (Aug 2006) ISSN: 1074-7613 [Print] United States
• PMID: 16872848 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Complement C3
• Intracellular Signaling Peptides and Proteins
• Ligands
• Macrophage-1 Antigen
• Reactive Oxygen Species
• Intercellular Adhesion Molecule-1
• NADPH Oxidases
• Protein-Tyrosine Kinases
• Syk Kinase
• Syk protein, mouse
• src-Family Kinases
• Peptide Hydrolases
• Pancreatic Elastase
• Matrix Metalloproteinases

Topics

• Animals
• Cell Adhesion
• Cell Movement
• Complement C3 (metabolism)
• Intercellular Adhesion Molecule-1 (metabolism)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Ligands
• Macrophage-1 Antigen (genetics, metabolism)
• Matrix Metalloproteinases (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NADPH Oxidases (metabolism)
• Neutrophils (cytology, enzymology)
• Pancreatic Elastase (metabolism)
• Peptide Hydrolases (metabolism)
• Protein-Tyrosine Kinases (metabolism)
• Reactive Oxygen Species (metabolism)
• Shwartzman Phenomenon (genetics, metabolism, pathology)
• Signal Transduction
• Syk Kinase
• Thrombosis (genetics, metabolism, pathology)
• src-Family Kinases (metabolism)