Mac-1 (CD11b/CD18) links inflammation and thrombosis after glomerular injury.
BACKGROUND
Inflammation and thrombosis coexist in several disorders. Although it is recognized that leukocytes may induce a procoagulant state at sites of inflammation, the critical molecular determinants of this process remain largely unknown.


RESULTS
To examine mechanisms of inflammation-induced thrombosis, we developed a murine model of thrombotic glomerulonephritis (TGN), a known cause of acute renal failure in patients. This model, induced by lipopolysaccharide and antibody to the glomerular basement membrane, led to rapid glomerular neutrophil recruitment, thrombotic glomerular lesions with endothelial cell injury, and renal dysfunction. In mice immunodepleted of neutrophils or lacking the leukocyte-specific integrin Mac-1, neutrophil recruitment, endothelial injury, glomerular thrombosis, and acute renal failure were markedly attenuated despite the robust generation of renal cytokines. Neutrophil elastase is a likely effector of Mac-1 because its activity was reduced in Mac-1-deficient mice and the phenotype in mice deficient in Mac-1 or neutrophil elastase was similar. Platelets accumulated in glomerular capillaries within 4 hours of TGN before evidence of thrombosis. Platelet immunodepletion before TGN markedly exacerbated hematuria (hemorrhage), inflammation, and injury, whereas thrombocytopenic Mac-1-deficient mice remained resistant to disease, indicating that initial glomerular platelet deposition protects the vessel wall from neutrophil-mediated sequelae. The subsequent thrombosis relied on the interaction of Mac-1 on recruited neutrophils with glycoprotein Ibalpha on platelets as antibody-mediated disruption of this interaction attenuated TGN without affecting renal neutrophil accumulation.


CONCLUSIONS
These observations establish Mac-1 on neutrophils as a critical molecular link between inflammation and thrombosis and suggest it as an attractive target for antithrombotic therapy.
Hirahashi
Junichi
J
Brigham and Women's Hospital, Department of Pathology, 77 Avenue Louis Pasteur, NRB752O, Boston, MA 02115, USA.
Hishikawa
Keiichi
K
Kaname
Shinya
S
Tsuboi
Naotake
N
Wang
Yunmei
Y
Simon
Daniel I
DI
Stavrakis
George
G
Shimosawa
Tatsuo
T
Xiao
Ling
L
Nagahama
Yutaka
Y
Suzuki
Kazuo
K
Fujita
Toshiro
T
Mayadas
Tanya N
TN
D058186:Acute Kidney Injury / Q000150:complications / Q000276:immunology / Q000473:pathology; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001792:Blood Platelets / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005921:Glomerulonephritis / Q000150:complications / Q000276:immunology* / Q000473:pathology; D019272:Leukocyte Elastase / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D013921:Thrombocytopenia / Q000276:immunology; D013927:Thrombosis / Q000209:etiology / Q000276:immunology* / Q000473:pathology
D000906:Antibodies; D016207:Cytokines; D016177:Macrophage-1 Antigen; D019038:Platelet Glycoprotein GPIb-IX Complex; D005337:Fibrin; D019272:Leukocyte Elastase