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Immunity. 2006 Aug;25(2):271-83. Epub 2006 Jul 27.

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

Author information

1
Department of Pathology, Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

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.

PMID:
16872848
DOI:
10.1016/j.immuni.2006.05.014
[Indexed for MEDLINE]
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