Journal
IMMUNITY
Volume 25, Issue 2, Pages 271-283Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2006.05.014
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Funding
- NHLBI NIH HHS [R01 HL041002, R37 HL41002, R01 HL54853, T32HL07627] Funding Source: Medline
- NIAID NIH HHS [R01 AI068150, AI065495] Funding Source: Medline
- NIAMS NIH HHS [R01 AR050800] Funding Source: Medline
- NIDDK NIH HHS [DK51643] Funding Source: Medline
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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 thrombo-hemorrhagic vasculitis, the CD18 integrin Mac-1 on neutrophils recognized complement C3 deposited within vessel walls and triggered a signaling pathway involving the Src-famlly 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.
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