Pan Bin, Wang Xiangmin, Kojima Shinsuke, Nishioka Chie, Yokoyama Akihito, Honda Goichi, Xu Kailin, Ikezoe Takayuki
Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Japan; Department of Hematology, Fukushima Medical University, Fukushima, Japan.
Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Japan.
Biol Blood Marrow Transplant. 2017 May;23(5):746-756. doi: 10.1016/j.bbmt.2017.02.001. Epub 2017 Feb 3.
Thrombomodulin (TM) exerts anti-inflammatory functions. We previously found that recombinant human soluble TM alleviated murine graft-versus-host disease (GVHD). Nevertheless, it is unclear how TM mediates its anti-inflammatory functions in GVHD. Here, we identified G-protein coupled receptor 15 (GPR15) expressed on T cells as a receptor/sensor of TM. The fifth region of epidermal growth factor-like domain of TM (TME5) bound GPR15 in vitro. TME5 prolonged survival of mice undergoing acute GVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TME5 increased regulatory T cells (Tregs) but decreased Th 1 proportions in targeted organs. TME5 suppressed allo-reaction in vitro in association with an increase in the number of induced Tregs. However, the anti-inflammatory function of TME5 was abolished when GPR15 knockout T cells were used as donor T cells. We further found that TME5 suppressed production of IL-6 in T cells, which probably facilitated differentiation of Tregs. Moreover, TME5 reduced activation of bone marrow-derived dendritic cells (BMDCs) and hampered function of BMDCs in inducing allo-reaction in vivo and in vitro. Our findings suggested that inducing Tregs as well as blocking activation of DCs in vivo by using TME5 is a potential therapeutic option for preventing GVHD in allo-HSCT.
血栓调节蛋白（TM）具有抗炎功能。我们之前发现重组人可溶性TM可减轻小鼠移植物抗宿主病（GVHD）。然而，TM在GVHD中如何介导其抗炎功能尚不清楚。在此，我们确定T细胞上表达的G蛋白偶联受体15（GPR15）为TM的受体/传感器。TM的表皮生长因子样结构域的第五区域（TME5）在体外与GPR15结合。TME5延长了异基因造血干细胞移植（allo-HSCT）后发生急性GVHD小鼠的生存期。TME5增加了调节性T细胞（Tregs）的数量，但降低了靶器官中Th1细胞的比例。TME5在体外抑制同种异体反应，同时诱导性Tregs数量增加。然而，当使用GPR15基因敲除的T细胞作为供体T细胞时，TME5的抗炎功能被消除。我们进一步发现，TME5抑制T细胞中IL-6的产生，这可能促进了Tregs的分化。此外，TME5降低了骨髓来源的树突状细胞（BMDCs）的活化，并阻碍了BMDCs在体内和体外诱导同种异体反应的功能。我们的研究结果表明，通过使用TME5在体内诱导Tregs以及阻断DCs的活化是预防allo-HSCT中GVHD的一种潜在治疗选择。
