Toll-Like Receptor 9 Signaling Is Critical for Early Experimental Deep Vein Thrombosis Resolution

DOI Web Site 3 Citations
  • Peter K. Henke
    From the Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, and Department of Pathology, University of Michigan Medical School, Ann Arbor, Mich.
  • Mayo Mitsuya
    From the Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, and Department of Pathology, University of Michigan Medical School, Ann Arbor, Mich.
  • Catherine E. Luke
    From the Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, and Department of Pathology, University of Michigan Medical School, Ann Arbor, Mich.
  • Megan A. Elfline
    From the Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, and Department of Pathology, University of Michigan Medical School, Ann Arbor, Mich.
  • Joseph F. Baldwin
    From the Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, and Department of Pathology, University of Michigan Medical School, Ann Arbor, Mich.
  • K. Barry Deatrick
    From the Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, and Department of Pathology, University of Michigan Medical School, Ann Arbor, Mich.
  • Jose A. Diaz
    From the Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, and Department of Pathology, University of Michigan Medical School, Ann Arbor, Mich.
  • Vikram Sood
    From the Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, and Department of Pathology, University of Michigan Medical School, Ann Arbor, Mich.
  • Gilbert R. Upchurch
    From the Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, and Department of Pathology, University of Michigan Medical School, Ann Arbor, Mich.
  • Thomas W. Wakefield
    From the Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, and Department of Pathology, University of Michigan Medical School, Ann Arbor, Mich.
  • Cory Hogaboam
    From the Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, and Department of Pathology, University of Michigan Medical School, Ann Arbor, Mich.
  • Steven L. Kunkel
    From the Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, and Department of Pathology, University of Michigan Medical School, Ann Arbor, Mich.

Description

<jats:sec> <jats:title>Objective—</jats:title> <jats:p> Toll-like receptors (TLR) bridge innate immunity and host responses, including inflammation. Sterile inflammation such as a venous thrombus (V <jats:sc>t</jats:sc> ) may involve TLR signaling, including TLR9. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> TLR9 signaling on thrombus resolution was investigated using a mouse model of stasis V <jats:sc>t</jats:sc> . V <jats:sc>t</jats:sc> were significantly larger in TLR9−/− mice compared with wild-type (WT) at 2 and 8 days, despite a 2-fold increase in thrombus polymorphonucleic neutrophils at 2 days and monocytes at 8 days, whereas thrombus collagen and neovascularization was 55% and 37% less, respectively, at 8 days. Coincidently, decreased fibrinogen and increased thrombin-antithrombin complex were observed in TLR9−/− mouse thrombi. Vein wall interferon-α, interleukin-1α, and interleukin-2 were significantly reduced in TLR9−/− mice compared with WT. Thrombus cell death pathway markers were not significantly altered at 2 days, but caspase-1 was reduced in TLR9−/− thrombi at 8 days. MyD88 confers TLR9 intracellular signaling, but MyD88−/− mice had V <jats:sc>t</jats:sc> resolution similar to that of WT. However, inhibition of the NOTCH ligand δ-like 4 was associated with larger V <jats:sc>t</jats:sc> . Finally, stimulation with a TLR9 agonist was associated with smaller V <jats:sc>t</jats:sc> . </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion—</jats:title> <jats:p> TLR9 signaling is integral for early and mid-V <jats:sc>t</jats:sc> resolution through modulation of sterile inflammation, maintaining a TH1 milieu, and effects on the thrombosis pathway. </jats:p> </jats:sec>

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