Intestinal iNKT cells migrate to liver and contribute to hepatocyte apoptosis during alcoholic liver disease
Intestinal iNKT cells migrate to liver and contribute to hepatocyte apoptosis during alcoholic liver disease
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DOI：
10.1152/ajpgi.00269.2018
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发表时间：
2019-05-01
影响因子：
4.5
通讯作者：
Schnabl, Bernd
中科院分区：
文献类型：
--
作者：
Lee, Kuei-Chuan;Chen, Peng;Schnabl, Bernd
我们研究了肠道免疫细胞向肝脏的迁移及其对酒精性肝病的贡献。在喂食乙醇的小鼠中，我们发现对CD 1d呈递的抗原有反应的不变自然杀伤T（iNKT）细胞数量增加，从肠系膜淋巴结迁移到肝脏。iNKT细胞与脂质抗原反应，因此我们研究了它们在具有肠上皮细胞特异性缺失Pparg（Pparg（Delta IEC））的小鼠中的活性，作为改变肠脂质组学特征的模型。在乙醇喂养的Pparg（Delta IEC）小鼠的肠道中，CD 1d水平增加，并且在细胞追踪实验中，与没有破坏Pparg的小鼠相比，更多的iNKT细胞迁移到肝脏。Pparg（Delta IEC）小鼠的肝脏在乙醇喂养后具有增加的细胞凋亡和肝损伤标记物。从乙醇喂养的Pparg（Delta IEC）小鼠的肝脏分离的iNKT细胞诱导培养的肝细胞的凋亡。iNKT细胞的抑制剂减少Pparg（Delta IEC）小鼠中乙醇诱导的肝损伤。酒精使用障碍患者的十二指肠组织中CD 1d的水平高于非酒精过度使用患者的组织。因此，乙醇的使用激活了肠道中的iNKT细胞迁移到肝脏，在那里它们与常驻的肝iNKT细胞一起导致肝细胞死亡和损伤。新&值得注意的是在这篇文章中，我们研究了肠道免疫细胞迁移到肝脏中响应乙醇诱导的肝脏疾病。我们发现，慢性乙醇喂养诱导肠上皮细胞表达CD 1d，从而激活肠系膜淋巴结中不变的自然杀伤T（iNKT）细胞;随着过氧化物酶体增殖物激活受体γ基因的丢失和脂质谱的改变，激活进一步增加。活化的iNKT细胞迁移到肝脏中，在那里它们促进肝细胞凋亡。酒精使用障碍患者小肠中CD 1d的表达增加。阻断这些过程的策略可能被开发用于治疗酒精性肝病。
We investigated the migration of intestinal immune cells to the liver and their contribution to alcoholic liver disease. In mice fed ethanol, we found that an increased number of invariant natural killer T (iNKT) cells, which respond to the antigen presented by CD1d, migrated from mesenteric lymph nodes to the liver. iNKT cells react to lipid antigens, so we studied their activities in mice with intestinal epithelial cell-specific deletion of Pparg (Pparg(Delta IEC)) as a model for altering intestinal lipidomic profiles. Levels of CD1d increased in intestines of ethanol-fed Pparg(Delta IEC) mice, and in cell-tracking experiments, more iNKT cells migrated to the liver, compared with mice without disruption of Pparg. Livers of Pparg(Delta IEC) mice had increased markers of apoptosis and liver injury after ethanol feeding. iNKT cells isolated from livers of ethanol-fed Pparg(Delta IEC) mice induced apoptosis of cultured hepatocytes. An inhibitor of iNKT cells reduced ethanol-induced liver injury in Pparg(Delta IEC) mice. Duodenal tissues from patients with alcohol-use disorder have been found to have increased levels of CD1d compared with tissues from patients without alcohol overuse. Ethanol use, therefore, activates iNKT cells in the intestine to migrate to liver, where they-along with the resident hepatic iNKT cells-contribute to hepatocyte death and injury.NEW & NOTEWORTHY In this article, we studied migration of intestinal immune cells into the liver in response to ethanol-induced liver disease. We found that chronic ethanol feeding induces expression of CD1d by enterocytes, which activate invariant natural killer T (iNKT) cells in mesenteric lymph nodes; activation is further increased with loss of peroxisome proliferator-activated receptor gamma gene and altered lipid profiles. The activated iNKT cells migrate into the liver, where they promote hepatocyte apoptosis. Patients with alcohol use disorder have increased expression of CD1d in the small intestine. Strategies to block these processes might be developed to treat alcoholic liver disease.