Thrombomodulin induces anti-inflammatory effects by inhibiting the rolling adhesion of leukocytes in vivo.
Thrombomodulin induces anti-inflammatory effects by inhibiting the rolling adhesion of leukocytes in vivo.
复制标题
血栓调节蛋白通过抑制体内白细胞的滚动粘附来诱导抗炎作用。
DOI：
10.1016/j.jphs.2020.01.001
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Ishii M.
中科院分区：
文献类型：
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作者：
Nishizawa S;Kikuta J;Seno S;Kajiki M;Tsujita R;Mizuno H;Sudo T;Ao T;Matsuda H;Ishii M.
血栓调节素（Thrombomodulin， TM）是一种表达于血管内皮细胞表面的整体膜蛋白，具有抑制血液凝固的作用。最近的研究表明，TM通过抑制白细胞募集而具有抗炎作用。然而，TMin在体内的实际作用方式尚不清楚。在这里，我们用活体成像技术描述了重组人可溶性TM （TM α fa）对活小鼠白细胞动力学的药理作用。在控制条件下，中性粒细胞在血管中表现出三种不同类型的粘附行为：1)“非粘附”，即细胞流动时不粘附血管；2)“滚动黏附”，细胞与内皮短暂相互作用；3)“紧密结合”，即细胞与内皮细胞紧密结合。与对照组相比，局部脂多糖刺激导致滚动黏附的频率增加，这种黏附不是均匀分布在血管壁上，而是发生在特定的内皮部位。在炎症条件下，TM α，特别是TM的凝集素样区域D1结构域，显著降低了滚动粘附的频率，但不影响紧密结合的数量。这是第一个证明TM α通过抑制中性粒细胞与血管内皮细胞的滚动粘附而发挥抗炎作用的研究。
Thrombomodulin (TM) is an integral membrane protein expressed on the surface of vascular endothelial cells that suppresses blood coagulation. Recent studies have shown that TM exhibits anti-inflammatory effects by inhibiting leukocyte recruitment. However, the actual modes of action of TMin vivoremain unclear. Here, we describe the pharmacological effects of recombinant human soluble TM (TM alfa) on leukocyte dynamics in living mice using intravital imaging techniques. Under control conditions, neutrophils exhibited three distinct types of adhesion behavior in vessels: 1) “non-adhesion”, in which cells flowed without vessel adhesion; 2) “rolling adhesion”, in which cells transiently interacted with the endothelium; and 3) “tight binding”, in which cells bound strongly to the endothelial cells. Compared to control conditions, local lipopolysaccharide stimulation resulted in an increased frequency of rolling adhesion that was not homogeneously distributed on vessel walls but occurred at specific endothelial sites. Under inflammatory conditions, TM alfa, particularly the D1 domain which is a lectin-like region of TM, significantly decreased the frequency of rolling adhesion, but did not influence the number of tight bindings. This was the first study to demonstrate that TM alfa exerts anti-inflammatory effects by inhibiting rolling adhesion of neutrophils to vascular endothelial cells in living mice.