Pan Bin, Wang Xiangmin, Kojima Shinsuke, Nishioka Chie, Yokoyama Akihito, Honda Goichi, Xu Kailin, Ikezoe Takayuki
Kailin Xu, MD, Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, #99 West Huaihai Road, Xuzhou 221002, China, Tel.: +86 516 8580 2382, Fax: +86 516 8560 1527, E-mail:
Takayuki Ikezoe, MD, Department of Hematology, Fukushima Medical University, 1 Hikariga-oka, Fukushima City 960-1295, Japan, Tel.: +81 24 547 1190, Fax: +81 24 548 1821, E-mail:
Thromb Haemost. 2017 Feb 28;117(3):570-579. doi: 10.1160/TH16-10-0762. Epub 2017 Jan 12.
Thrombomodulin (TM) exerts cytoprotection via the fifth region of epidermal growth factor (EGF)-like domain of TM (TME5) by interacting with G-protein coupled receptor 15 (GPR15) expressed on cell surface of vascular endothelial cells. TM is also implied to mediate anti-inflammatory functions by unknown mechanism. By applying a lipopolysaccharide (LPS)-induced murine sepsis model, we assessed the role of TME5 in septic inflammation and coagulation. We found that TME5 treatment protected mice in association with ameliorating inflammation and coagulopathy in LPS-induced sepsis. Further study confirmed that TME5 bound GPR15 in vitro. Knock out of GPR15 abolished protective role of TME5 in sepsis model. GPR15 mediated anti-inflammatory function of TME5 through suppression of phosphorylation of IκBα, nuclear translocation of NF-κB and release of pro-inflammatory cytokines in macrophages (Macs). Knock out of GPR15 resulted in dysregulated immune response of Macs, characterised by excessive expression of pro-inflammatory genes and failing to limit immune response. This study indicates that TME5 exerts anti-inflammatory function through inhibition of NF-κB in a GPR15-dependent manner. The use of TME5 may be a potential therapeutic option for treatment of sepsis.
血栓调节蛋白（TM）通过与血管内皮细胞表面表达的G蛋白偶联受体15（GPR15）相互作用，经由TM的表皮生长因子（EGF）样结构域的第五区域（TME5）发挥细胞保护作用。TM还被认为通过未知机制介导抗炎功能。通过应用脂多糖（LPS）诱导的小鼠脓毒症模型，我们评估了TME5在脓毒症炎症和凝血中的作用。我们发现，TME5治疗可保护小鼠，同时改善LPS诱导的脓毒症中的炎症和凝血病。进一步研究证实，TME5在体外与GPR15结合。敲除GPR15消除了TME5在脓毒症模型中的保护作用。GPR15通过抑制巨噬细胞（Macs）中IκBα的磷酸化、NF-κB的核转位和促炎细胞因子的释放来介导TME5的抗炎功能。敲除GPR15导致Macs的免疫反应失调，其特征是促炎基因过度表达且无法限制免疫反应。本研究表明，TME5以GPR15依赖的方式通过抑制NF-κB发挥抗炎功能。使用TME5可能是治疗脓毒症的一种潜在治疗选择。
