Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride.
Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride.
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DOI：
10.1002/hep.22813
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发表时间：
2009-05
期刊：
影响因子：
13.5
通讯作者：
Gao, Bin
中科院分区：
文献类型：
--
作者：
Park, Ogyi;Jeong, Won-Il;Wang, Lei;Wang, Hua;Lian, Zhe-Xiong;Gershwin, M. Eric;Gao, Bin
肝纤维化是所有形式的慢性肝损伤的常见疤痕反应，并且总是与导致纤维化的炎症有关。尽管在炎症过程中有多种细胞群渗入肝脏，但普遍清楚的是，CD8T淋巴细胞促进而自然杀伤细胞(NK)抑制肝纤维化。然而，肝脏中丰富的不变NKT(INKT)细胞在肝纤维化形成中的作用尚不清楚。在这里，我们表明iNKT缺陷的小鼠更容易受到四氯化碳(CCl4)诱导的急性肝损伤和炎症的影响。自然激活的iNKT在该模型中的保护作用可能是通过抑制激活的肝星状细胞的促炎效应来实现的。有趣的是，通过注射iNKT激活剂α-半乳糖基神经酰胺(α-GalCer)而强烈激活iNKT可加速CCl_4诱导的急性肝损伤和纤维化。相反，在注射CCl4后2周而不是4周，尽管iNKT细胞能够杀死激活的Stallate细胞，但慢性给予CCl4诱导了iNKT缺陷小鼠和野生型小鼠相似程度的肝损伤，而iNKT缺陷小鼠的肝纤维化程度仅略高于野生型小鼠。INKT在慢性肝损伤和肝纤维化中的作用不明显，可能是由于肝脏iNKT细胞耗尽所致。最后，慢性α-GalCer治疗对肝损伤和纤维化的影响不大，这是由于α-GalCer注射后对iNKT的耐受所致。肝脏iNKT细胞的自然激活抑制了iNKT细胞的激活，而α-GalCer对iNKT细胞的强烈激活加速了CCl_4诱导的急性肝损伤、炎症和纤维化。在慢性肝损伤过程中，肝脏iNKT细胞被耗尽，并在肝纤维化的早期发挥抑制作用，而在肝纤维化的晚期则不起作用。
Liver fibrosis is a common scarring response to all forms of chronic liver injury and is always associated with inflammation that contributes to fibrogenesis. Although a variety of cell populations infiltrate the liver during inflammation, it is generically clear that CD8 T lymphocytes promote while natural killer (NK) cells inhibit liver fibrosis. However, the role of invariant NKT (iNKT) cells, which are abundant in the liver, in hepatic fibrogenesis, remains obscure. Here we show that iNKT-deficient mice are more susceptible to carbon tetrachloride (CCl4)-induced acute liver injury and inflammation. The protective effect of naturally activated iNKT in this model is likely mediated via suppression of the proinflammatory effect of activated hepatic stellate cells. Interestingly, strong activation of iNKT through injection of iNKT activator α-galactosylceramide (α-GalCer) accelerates CCl4-induced acute liver injury and fibrosis. In contrast, chronic CCl4 administration induced a similar degree of liver injury in iNKT-deficient and wild-type mice, and only slightly higher grade of liver fibrosis in iNKT-deficient mice than wild-type mice 2 weeks but not 4 weeks post CCl4 injection although iNKT cells are able to kill activated stallate cells. An insignificant role of iNKT in chronic liver injury and fibrosis may be due to hepatic iNKT cell depletion. Finally, chronic α-GalCer treatment had little effect on liver injury and fibrosis, which is due to iNKT tolerance after α-GalCer injection. natural activation of hepatic iNKT cells inhibits while strong activation of iNKT cells by α-GalCer accelerates CCl4-induced acute liver injury, inflammation, and fibrosis. During chronic liver injury, hepatic iNKT cells are depleted and play a role in inhibiting liver fibrosis in the early stage but not the late stage of fibrosis.
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