Lack of T-bet reduces monocytic interleukin-12 formation and accelerates thrombus resolution in deep vein thrombosis.
Lack of T-bet reduces monocytic interleukin-12 formation and accelerates thrombus resolution in deep vein thrombosis.
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DOI：
10.1038/s41598-018-21273-5
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发表时间：
2018-02-14
影响因子：
4.6
通讯作者：
Wenzel P
中科院分区：
文献类型：
--
作者：
Schönfelder T;Brandt M;Kossmann S;Knopp T;Münzel T;Walter U;Karbach SH;Wenzel P
白细胞在深静脉血栓形成(DVT)消退中的作用尚不完全清楚。我们确定了溶菌酶阳性(LysM+)细胞的耗尽和关闭的1型免疫反应是如何影响血栓溶解的。12周龄雄性小鼠下腔静脉(IVC)狭窄诱发DVT。毒素介导的髓系细胞耗竭通过Cre诱导的LysM+细胞中白喉毒素受体的表达改善了小鼠血栓的溶解。这与CD45+细胞减少、Gr-1+向Gr-1−CD11b+粒单核细胞群转移(流式细胞术)以及CC-趋化因子配体2、IL-4和IL-10mRNA表达增加有关。Tbx21−/−小鼠(缺乏转录因子T-bet，以1型免疫反应减弱为标志)与对照组小鼠相比，血栓溶解更快，血栓中促炎症的Ly6chi单核细胞减少，IL-12p40mRNA表达降低，导致血管内皮生长因子基因表达增加，血栓静脉新生血管改善。将Tbx21−/−骨髓移植到照射后的Tbx21+/+受体体内，可加速血栓的溶解，并降低下腔静脉狭窄后T-bet依赖的白细胞介素12p40mRNA水平。我们的结论是，抑制Tbet+IL-12形成粒单核细胞加速了血栓的溶解。调节炎症免疫反应可能是改善DVT治疗的途径之一。
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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影响因子：
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作者：
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