TRAIL-producing NK cells contribute to liver injury and related fibrogenesis in the context of GNMT deficiency.
TRAIL-producing NK cells contribute to liver injury and related fibrogenesis in the context of GNMT deficiency.
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DOI：
10.1038/labinvest.2014.151
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发表时间：
2015-02
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甘氨酸-N-甲基转移酶(GNMT)是维持肝脏动态平衡所必需的。因此，肝硬变患者表现出肝细胞癌标本中没有的GNMT的低表达。因此，小鼠缺乏GNMT会导致脂肪性肝炎、纤维化、肝硬变和肝细胞癌。缺乏GNMT可触发GNMT−/−小鼠的NK细胞活化，而TRAIL的耗竭可显著减轻这些动物的急性肝损伤和炎症。慢性炎症导致纤维化，进一步促进慢性肝损伤的进展，无论其病因如何。综上所述，我们的研究目的是阐明产生TRAIL的NK细胞在慢性肝损伤和纤维化进展中的意义。为此，我们产生了双TRAIL−/−/GNMT−/−小鼠，我们发现在GNMT缺乏的情况下，TRAIL缺乏有效地保护肝脏免受慢性肝损伤和纤维化的影响。接下来，为了更好地描述TRAIL产生的NK细胞在纤维化形成过程中的意义，我们对GNMT−/−和TRAIL−/−/GNMT−/−小鼠进行了胆管结扎。在GNMT−/−小鼠中，骨髓间充质干细胞同时激活NK1.1+细胞后，肝纤维化反应加重。重要的是，对产生TRAIL的NK细胞的特异性抑制有效地保护了GNMT−/−小鼠免受bdl诱导的肝损伤和纤维化。最后，TRAIL−/−/GNMT−/−组小鼠肝纤维化程度明显低于−/−组小鼠，进一步强调TRAIL/DR5轴在介导−/−小鼠肝损伤和纤维化形成中的作用。最后，体内沉默DR5有效地保护−/−小鼠免受肝损害和肝纤维化的影响，总体上强调了TRAIL/DR5轴在缺乏GNMT的情况下促进肝纤维化的关键作用。总体而言，我们的工作表明，在GNMT缺乏症的病理背景下，产生TRAIL的NK细胞积极促进肝脏损伤和进一步的纤维化形成，GNMT缺乏症是慢性人类肝病的分子特征。
Glycine-N-methyltransferase (GNMT) is essential to preserve liver homeostasis. Thus, cirrhotic patients show low expression of GNMT that is absent in HCC samples. Accordingly, GNMT deficiency in mice leads to steatohepatitis, fibrosis, cirrhosis and HCC. Lack of GNMT triggers NK cell activation in GNMT−/− mice and depletion of TRAIL significantly attenuates acute liver injury and inflammation in these animals. Chronic inflammation leads to fibrogenesis, further contributing to the progression of chronic liver injury regardless of the etiology. Taking all this together, the aim of our study is to elucidate the implication of TRAIL-producing NK cells in the progression of chronic liver injury and fibrogenesis. For this we generated double TRAIL−/−/GNMT−/− mice where we found that TRAIL deficiency efficiently protected the liver against chronic liver injury and fibrogenesis in the context of GNMT deficiency. Next, to better delineate the implication of TRAIL-producing NK cells during fibrogenesis we performed bile duct ligation (BDL) to GNMT−/− and TRAIL−/−/GNMT−/− mice. In GNMT−/− mice, exacerbated fibrogenic response after BDL concurred with NK1.1+ cell activation. Importantly, specific inhibition of TRAIL-producing NK cells efficiently protected GNMT−/− mice from BDL-induced liver injury and fibrogenesis. Finally, TRAIL−/−/GNMT−/− showed significantly less fibrosis after BDL than GNMT−/− mice further underlining the relevance of the TRAIL/DR5 axis in mediating liver injury and fibrogenesis in GNMT−/− mice. Finally, in vivo silencing of DR5 efficiently protected GNMT−/− mice from BDL-liver injury and fibrogenesis, overall underscoring the key role of the TRAIL/DR5 axis in promoting fibrogenesis in the context of absence of GNMT. Overall, our work demonstrates that TRAIL-producing NK cells actively contribute to liver injury and further fibrogenesis in the pathological context of GNMT deficiency, a molecular scenario characteristic of chronic human liver disease.