title: 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.affiliation: Department of Pathology, Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Junichi
authors.initials: J
authors.lastname: Hirahashi
authors.forename: Divya
authors.initials: D
authors.lastname: Mekala
authors.forename: Jessica
authors.initials: J
authors.lastname: Van Ziffle
authors.forename: Ling
authors.initials: L
authors.lastname: Xiao
authors.forename: Simin
authors.initials: S
authors.lastname: Saffaripour
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: Clifford
authors.initials: C
authors.lastname: Lowell
authors.forename: Tanya N
authors.initials: TN
authors.lastname: Mayadas
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D003176:Complement C3 / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008024:Ligands; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology; D010196:Pancreatic Elastase / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012790:Shwartzman Phenomenon / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D000072377:Syk Kinase; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D003176:Complement C3; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D016177:Macrophage-1 Antigen; D017382:Reactive Oxygen Species; D018799:Intercellular Adhesion Molecule-1; D019255:NADPH Oxidases; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D019061:src-Family Kinases; D010447:Peptide Hydrolases; D010196:Pancreatic Elastase; D020782:Matrix Metalloproteinases