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Sci Rep. 2018 Feb 14;8(1):3013. doi: 10.1038/s41598-018-21273-5.

Lack of T-bet reduces monocytic interleukin-12 formation and accelerates thrombus resolution in deep vein thrombosis.

Author information

1
Center for Thrombosis and Hemostasis Mainz, Mainz, Germany.
2
Center for Cardiology-Cardiology I, Mainz, Germany.
3
Deutsches Zentrum für Herzkreislaufforschung (DZHK)-Partner site Rhine-Main, University Medical Center Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
4
Center for Thrombosis and Hemostasis Mainz, Mainz, Germany. wenzelp@uni-mainz.de.
5
Center for Cardiology-Cardiology I, Mainz, Germany. wenzelp@uni-mainz.de.
6
Deutsches Zentrum für Herzkreislaufforschung (DZHK)-Partner site Rhine-Main, University Medical Center Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany. wenzelp@uni-mainz.de.

Abstract

The role of leukocytes in deep vein thrombosis (DVT) resolution is incompletely understood. We determined how depletion of lysozyme positive (LysM+) cells and a switched-off type 1 immune response influences thrombus resolution. DVT was induced in 12-week-old male mice by inferior vena cava (IVC) stenosis. Toxin mediated depletion of myeloid cells improved thrombus resolution in mice with Cre-inducible expression of the diphtheria toxin receptor in LysM+ cells. This correlated with decreased CD45+ cells, a population shift of Gr-1+ to Gr-1- CD11b+ myelomonocytic cells (flow cytometry) and an increase in CC-chemokine ligand 2, interleukin-4 and interleukin-10 mRNA expressions. Tbx21-/- mice (lacking transcription factor T-bet and marked by an attenuated type 1 immune response) with DVT had faster thrombus resolution, a reduction of pro-inflammatory Ly6Chi monocytes in thrombi and decreased interleukin-12p40 mRNA expression than control mice resulting in increased vascular endothelial growth factor mRNA expression and improved neovascularization of thrombotic veins. Transfer of Tbx21-/- bone marrow into irradiated Tbx21+/+ recipients lead to accelerated thrombus resolution with lower T-bet-dependent interleukin-12p40 mRNA levels following IVC-stenosis. We conclude that inhibition of Tbet+ interleukin-12 forming myelomonocytic cells accelerated thrombus resolution. Modulating the inflammatory immune response might be an approach to improve therapy of DVT.

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