TY - JOUR
T1 - Mac-1 Signaling via Src-Family and Syk Kinases Results in Elastase-Dependent Thrombohemorrhagic Vasculopathy
AU - Hirahashi, Junichi
AU - Mekala, Divya
AU - Van Ziffle, Jessica
AU - Xiao, Ling
AU - Saffaripour, Simin
AU - Wagner, Denisa D.
AU - Shapiro, Steven D.
AU - Lowell, Clifford
AU - Mayadas, Tanya N.
N1 - Funding Information:
We are grateful to Xavier Cullere (Brigham and Women's Hospital) for helpful suggestions and critical reading of the manuscript. We would also like to thank the following investigators for generously providing gene mutant mice: Dr. Caroline Owen (Brigham and Women's Hospital, Boston, MA) for mice deficient in both MMP8 and MMP9, and Dr. Michael Carroll (CBR Institute for Biomedical Research, Boston, MA) for complement C3 −/− mice. This work was supported by an AHA Established Investigator Award (T.N.M.), the Uehara Memorial Foundation, Japan (J.H.), the T32HL07627 (D.M.), NIH RO1 AR050800 and DK51643 (T.N.M.), RO1 AI068150 and AI065495 (C.L.), R37 HL41002 (D.D.W.), and R01 HL54853 (S.D.S.).
PY - 2006/8
Y1 - 2006/8
N2 - 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.
AB - 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.
KW - HUMDISEASE
KW - MOLIMMUNO
KW - SIGNALING
UR - http://www.scopus.com/inward/record.url?scp=33747150762&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33747150762&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2006.05.014
DO - 10.1016/j.immuni.2006.05.014
M3 - Article
C2 - 16872848
AN - SCOPUS:33747150762
SN - 1074-7613
VL - 25
SP - 271
EP - 283
JO - Immunity
JF - Immunity
IS - 2
ER -
