Divergent effects of Tlr9 deletion in experimental late venous thrombosis resolution and vein wall injury

Nicholas A. Dewyer; Osama M. El-Sayed; Catherine E. Luke; Megan Elfline; Nicolai Kittan; Ron Allen; Adriana Laser; Carson Oostra; Anthony Comerota; Cory Hogaboam; Steven L. Kunkel; Peter K. Henke

doi:10.1160/TH14-12-1031

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2015; 114(05): 1028-1037
DOI: 10.1160/TH14-12-1031

Blood Cells, Inflammation and Infection

Schattauer GmbH

Divergent effects of Tlr9 deletion in experimental late venous thrombosis resolution and vein wall injury

Autor*innen

Nicholas A. Dewyer^*

¹Department of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
Osama M. El-Sayed^*

¹Department of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
Catherine E. Luke

¹Department of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
Megan Elfline

¹Department of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
Nicolai Kittan

²Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
Ron Allen

²Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
Adriana Laser

¹Department of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
Carson Oostra

³Jobst Vascular Institute, Toledo Hospital, Toledo, Michigan, USA
Anthony Comerota

³Jobst Vascular Institute, Toledo Hospital, Toledo, Michigan, USA
Cory Hogaboam

²Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
Steven L. Kunkel

²Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
Peter K. Henke

¹Department of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA

Abstract

Summary

Deep-vein thrombosis (DVT) resolves via a sterile inflammatory response. Defining the inflammatory response of DVT may allow for new therapies that do not involve anticoagulation. Previously, we have shown that Toll-like receptor 9 (Tlr9) gene deleted mice had impaired venous thrombosis (VT) resolution. Here, we further characterise the role of Tlr9 signalling and sterile inflammation in chronic VT and vein wall responses. First, we found a human precedent exists with Tlr9 ⁺ cells present in chronic post thrombotic intraluminal tissue. Second, in a stasis VT mouse model, endogenous danger signal mediators of uric acid, HMGB-1, and neutrophil extracellular traps marker of citrullinated histone-3 (and extracellular DNA) were greater in Tlr9^-/- thrombi as compared with wild-type (WT), corresponding with larger VT at 8 and 21 days. Fewer M1 type (CCR2+) monocyte/macrophages (MØ) were present in Tlr9^-/- thrombi than WT controls at 8 days, suggesting an impaired inflammatory cell influx. Using bone marrow-derived monocyte (BMMØ) cell culture, we found decreased fibrinolytic gene expression with exposure to several endogenous danger signals. Next, adoptive transfer of cultured Tlr9^+/+ BMMØ to Tlr9^-/- mice normalised VT resolution at 8 days. Lastly, although the VT size was larger at 21 days in Tlr9^-/- mice and correlated with decreased endothelial antigen markers, no difference in fibrosis was found. These data suggest that Tlr9 signalling in MØ is critical for later VT resolution, is associated with necrosis clearance, but does not affect later vein wall fibrosis. These findings provide insight into the Tlr9 MØ mechanisms of sterile inflammation in this disease process.

Keywords

Animal models - deep-vein thrombosis - inflammation - venous thrombosis

Volltext

Referenzen

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