The chemokine scavenging receptor D6 limits acute toxic liver injury in vivo
The chemokine scavenging receptor D6 limits acute toxic liver injury in vivo
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DOI：
10.1515/bc.2009.119
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发表时间：
2009-10-01
影响因子：
3.7
通讯作者：
Wasmuth, Hermann E.
中科院分区：
文献类型：
--
作者：
Berres, Marie-Luise;Trautwein, Christian;Wasmuth, Hermann E.
趋化因子诱饵受体D6是一种混杂的趋化因子受体，缺乏经典的信号功能。它通过将CC趋化因子靶向于细胞内化和降解来负性调节炎症。本研究分析了D6在组成型D6（-/-）和野生型小鼠急性ccl4诱导的肝损伤中的功能。通过肝脏组织学、血清转氨酶、IL-6和TNF α mRNA表达来评估肝损伤程度。采用elisa法检测肝脏内D6配体（CCL2、CCL3、CCL5）和非D6配体CXCL9的蛋白水平。肝内免疫细胞浸润用流式细胞仪（FACS）表征。D6基因缺失导致急性CCl4给药后肝损伤延长。D6（-/-）小鼠的肝损伤增强与48小时后肝内炎症趋化因子CCL2、CCL3和CCL5蛋白水平升高有关，而CXCL9在敲除小鼠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，主要鉴定为T细胞和NK细胞。综上所述，趋化因子清道夫受体D6在体内急性中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。
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 CCl4-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 TNF alpha 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 CCl4 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 intrahepatic 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.