Medical Department III, University Hospital Aachen, D-52074 Aachen, Germany.
Biol Chem. 2009 Oct;390(10):1039-45. doi: 10.1515/BC.2009.119.
The chemokine decoy receptor D6 is a promiscuous chemokine receptor lacking classical signaling functions. It negatively regulates inflammation by targeting CC chemokines to cellular internalization and degradation. Here we analyze the function of D6 in acute CCl(4)-induced liver damage in constitutive D6(-/-) and wild-type mice. The degree of liver injury was assessed by liver histology, serum transaminases, IL-6, and TNFalpha mRNA expression. Protein levels of D6 ligands (CCL2, CCL3, CCL5) and the non-D6-ligand CXCL9 within the livers were determined by ELISAs. The intrahepatic infiltration of immune cells was characterized by FACS. Genetic deletion of D6 led to prolonged liver damage after acute CCl(4) administration. The augmented liver damage in D6(-/-) mice was associated with increased protein levels of intrahepatic inflammatory chemokines CCL2, CCL3, and CCL5 after 48 h, whereas CXCL9 was not different between knockout and wild-type mice. Functionally, increased intra-hepatic CC chemokine concentrations led to increased infiltration of CD45(+) leukocytes, which were mainly identified as T and NK cells. In conclusion, the chemokine scavenger receptor D6 has a non-redundant role in acute toxic liver injury in vivo. These results support the importance of post-translational chemokine regulation and describe a new mechanism of immune modulation within the liver.
趋化因子诱饵受体 D6 是一种混杂的趋化因子受体，缺乏经典的信号转导功能。它通过将 CC 趋化因子靶向细胞内化和降解来负调控炎症。在这里，我们分析了 D6 在 CCl(4)诱导的急性肝损伤中的功能缺失，在组成性 D6(-/-)和野生型小鼠中进行了分析。通过肝组织学、血清转氨酶、IL-6 和 TNFalpha mRNA 表达来评估肝损伤的程度。通过 ELISA 测定肝脏中 D6 配体（CCL2、CCL3、CCL5）和非 D6 配体 CXCL9 的蛋白水平。通过 FACS 对肝内免疫细胞的浸润进行了表征。D6 的遗传缺失导致急性 CCl(4)给药后肝脏损伤延长。D6(-/-)小鼠的肝损伤加剧与 48 小时后肝内炎症趋化因子 CCL2、CCL3 和 CCL5 的蛋白水平增加有关，而 CXCL9 在敲除和野生型小鼠之间没有差异。功能上，肝内 CC 趋化因子浓度的增加导致 CD45(+)白细胞的浸润增加，这些白细胞主要被鉴定为 T 和 NK 细胞。总之，趋化因子清除受体 D6 在体内急性毒性肝损伤中具有非冗余作用。这些结果支持了翻译后趋化因子调节的重要性，并描述了肝脏内免疫调节的新机制。
