CCR5 knockout mice with C57BL6 background are resistant to acetaminophen-mediated hepatotoxicity due to decreased macrophages migration into the liver
CCR5 knockout mice with C57BL6 background are resistant to acetaminophen-mediated hepatotoxicity due to decreased macrophages migration into the liver
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DOI：
10.1007/s00204-014-1253-3
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发表时间：
2015-02-01
影响因子：
6.1
通讯作者：
Hong, Jin Tae
中科院分区：
文献类型：
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作者：
Choi, Dong-Young;Ban, Jung-Ok;Hong, Jin Tae
过量的醋氨酚（APAP）会导致肝小叶中心细胞坏死。越来越多的证据表明，先天免疫系统可能参与了APAP诱导的肝毒性。RANTES与其受体C-C趋化因子受体（CCR）5之间的相互作用与巨噬细胞向炎症部位的募集有关。在这项研究中，我们研究了CCR 5缺陷对APAP介导的肝损伤的影响，采用CCR 5敲除（KO）小鼠。CCR 5野生型（WT）和KO小鼠接受腹膜内注射APAP（300 mg/kg），并在注射后24 h处死。通过组织学和生化分析确定肝损伤。通过苏木精和伊红染色以及血清中丙氨酸转氨酶和天冬氨酸转氨酶水平的增加证明，腹膜内APAP引起肝细胞坏死。与KO动物相比，CCR 5 WT动物的肝损伤似乎更大。CCR 5 WT和KO动物之间细胞色素P450 2 E1无差异，表明CCR 5 KO小鼠的耐药性并非来自APAP代谢的改变。在CCR 5 KO小鼠中，巨噬细胞向肝脏的浸润减少，并且这伴随着炎症反应的减少。预处理氯化钆抑制巨噬细胞活性可显著阻断APAP引起的肝毒性。这些结果表明，巨噬细胞募集到炎症部位显着有助于APAP介导的肝细胞死亡和CCR 5基因缺失保护APAP诱导的肝损伤，减轻巨噬细胞募集和炎症反应。这项研究代表了CCR 5在APAP攻击后巨噬细胞浸润到肝脏和随后的肝毒性中的关键作用。
Overdose of acetaminophen (APAP) causes necrosis of centrilobular cells of the liver. Accumulating evidence suggests that innate immune system may contribute to APAP-induced hepatotoxicity. Interaction between RANTES and its receptor C-C chemokine receptor (CCR) 5 is related to recruitment of macrophages to sites of inflammation. In this study, we examined effects of CCR5 deficiency on APAP-mediated liver injury by employing CCR5 knockout (KO) mice. CCR5 wild-type (WT) and KO mice received intraperitoneal injection of APAP (300 mg/kg) and were killed 24 h after the injection. Hepatic injury was determined by using histological and biochemical analyses. Intraperitoneal APAP caused the hepatocytic necrosis, as evidenced by hematoxylin and eosin staining and an increase in alanine transaminase and aspartate transaminase levels in serum. Hepatic damage appeared to be larger in CCR5 WT animals compared with KO animals. There were no differences in cytochrome P450 2E1 between CCR5 WT and KO animals suggesting that the resistance of CCR5 KO mice did not come from alterations in APAP metabolism. Infiltration of macrophages into the liver was reduced in CCR5 KO mice, and this was accompanied decreased inflammatory responses. Inhibition of macrophage activity by pretreatment of gadolinium chloride significantly blocked APAP-caused hepatotoxicity. These results indicate that recruitment of macrophage into the inflammatory sites significantly contributes to APAP-mediated hepatocytic death and CCR5 gene deletion protects from APAP-induced liver injury by alleviating macrophage recruitment and inflammatory responses. This study represents a critical role of CCR5 in macrophage infiltration into the liver and subsequent hepatotoxicity upon challenge of APAP.