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

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 Ly6C 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.