Mac-1 (CD11b/CD18) links inflammation and thrombosis after glomerular injury

Junichi Hirahashi, Keiichi Hishikawa, Shinya Kaname, Naotake Tsuboi, Yunmei Wang, Daniel I. Simon, George Stavrakis, Tatsuo Shimosawa, Ling Xiao, Yutaka Nagahama, Kazuo Suzuki, Toshiro Fujita, Tanya N. Mayadas

Research output: Contribution to journalArticle

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Abstract

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. METHODS AND 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 Ibα 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.

Original languageEnglish
Pages (from-to)1255-1265
Number of pages11
JournalCirculation
Volume120
Issue number13
DOIs
Publication statusPublished - 2009 Sep
Externally publishedYes

Fingerprint

Thrombosis
Glomerulonephritis
Inflammation
Neutrophils
Wounds and Injuries
Blood Platelets
Leukocyte Elastase
Neutrophil Infiltration
Kidney
Acute Kidney Injury
Leukocytes
Platelet Glycoprotein GPIb-IX Complex
Glomerular Basement Membrane
Antibodies
Hematuria
Integrins
Lipopolysaccharides
Endothelial Cells
Hemorrhage
Cytokines

Keywords

  • Cell adhesion molecules
  • Inflammation
  • Kidney
  • Leukocytes
  • Thrombosis

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Hirahashi, J., Hishikawa, K., Kaname, S., Tsuboi, N., Wang, Y., Simon, D. I., ... Mayadas, T. N. (2009). Mac-1 (CD11b/CD18) links inflammation and thrombosis after glomerular injury. Circulation, 120(13), 1255-1265. https://doi.org/10.1161/CIRCULATIONAHA.109.873695

Mac-1 (CD11b/CD18) links inflammation and thrombosis after glomerular injury. / Hirahashi, Junichi; Hishikawa, Keiichi; Kaname, Shinya; Tsuboi, Naotake; Wang, Yunmei; Simon, Daniel I.; Stavrakis, George; Shimosawa, Tatsuo; Xiao, Ling; Nagahama, Yutaka; Suzuki, Kazuo; Fujita, Toshiro; Mayadas, Tanya N.

In: Circulation, Vol. 120, No. 13, 09.2009, p. 1255-1265.

Research output: Contribution to journalArticle

Hirahashi, J, Hishikawa, K, Kaname, S, Tsuboi, N, Wang, Y, Simon, DI, Stavrakis, G, Shimosawa, T, Xiao, L, Nagahama, Y, Suzuki, K, Fujita, T & Mayadas, TN 2009, 'Mac-1 (CD11b/CD18) links inflammation and thrombosis after glomerular injury', Circulation, vol. 120, no. 13, pp. 1255-1265. https://doi.org/10.1161/CIRCULATIONAHA.109.873695
Hirahashi, Junichi ; Hishikawa, Keiichi ; Kaname, Shinya ; Tsuboi, Naotake ; Wang, Yunmei ; Simon, Daniel I. ; Stavrakis, George ; Shimosawa, Tatsuo ; Xiao, Ling ; Nagahama, Yutaka ; Suzuki, Kazuo ; Fujita, Toshiro ; Mayadas, Tanya N. / Mac-1 (CD11b/CD18) links inflammation and thrombosis after glomerular injury. In: Circulation. 2009 ; Vol. 120, No. 13. pp. 1255-1265.
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AU - Wang, Yunmei

AU - Simon, Daniel I.

AU - Stavrakis, George

AU - Shimosawa, Tatsuo

AU - Xiao, Ling

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AU - Suzuki, Kazuo

AU - Fujita, Toshiro

AU - Mayadas, Tanya N.

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AB - 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. METHODS AND 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 Ibα 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.

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KW - Kidney

KW - Leukocytes

KW - Thrombosis

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