Inhibition of type I natural killer T cells by retinoids or following sulfatide-mediated activation of type II natural killer T cells attenuates alcoholic liver disease in mice.
Inhibition of type I natural killer T cells by retinoids or following sulfatide-mediated activation of type II natural killer T cells attenuates alcoholic liver disease in mice.
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DOI：
10.1002/hep.27632
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发表时间：
2015-04
期刊：
影响因子：
13.5
通讯作者：
Kumar, Vipin
中科院分区：
文献类型：
--
作者：
Maricic, Igor;Sheng, Huiming;Marrero, Idania;Seki, Ekihiro;Kisseleva, Tatiana;Chaturvedi, Som;Molle, Natasha;Mathews, Stephanie A.;Gao, Bin;Kumar, Vipin
先天免疫机制导致肝损伤后慢性酒精摄入知之甚少。自然杀伤T（NKT）细胞，在肝脏中富集，并包括至少两个不同的子集，I型和II型，识别不同的脂质抗原提出的CD 1d分子。我们研究了NKT细胞亚群的差异活化是否协调了导致酒精性肝病（ALD）的炎症事件。我们发现，在雄性C57 BL/6小鼠中长期加暴食Lieber-DeCarli流质饮食后，I型而非II型NKT细胞被激活，导致炎症性Gr-1highCD 11b+细胞募集到肝脏中。一个重要的发现是，酒精喂养后的肝损伤依赖于I型NKT细胞。因此，在I型NKT细胞缺陷的Jα18−/−小鼠中，以及在通过硫苷脂介导的II型NKT细胞活化而使其失活后，肝损伤被显著抑制。此外，我们已经确定了一种新的途径，涉及全反式维甲酸（ATRA）及其受体RARγ信号转导抑制I型NKT细胞，从而ALD。对人类疾病中共有的一些关键促炎分子的肝脏基因表达的半定量PCR分析表明，它们在ALD中的上调依赖于I型NKT细胞。I型而非II型NKT细胞在酒精喂养后被激活。I型NKT细胞诱导的炎症和中性粒细胞募集导致肝组织损伤，而II型NKT细胞保护ALD免受损伤。类维生素A或硫苷脂抑制I型NKT细胞可预防ALD。由于CD 1d途径在小鼠和人类之间高度保守，因此NKT细胞亚群可能成为ALD潜在治疗干预的目标。
Innate immune mechanisms leading to liver injury following chronic alcohol ingestion are poorly understood. Natural killer T (NKT) cells, enriched in the liver and comprised of at least two distinct subsets, type I and type II, recognize different lipid antigens presented by CD1d molecules. We have investigated whether differential activation of NKT cell subsets orchestrates inflammatory events leading to alcoholic liver disease (ALD). We found that following chronic plus binge feeding of Lieber-DeCarli liquid diet in male C57BL/6 mice, type I but not type II NKT cells are activated leading to recruitment of inflammatory Gr-1highCD11b+ cells into liver. A central finding is that liver injury following alcohol feeding is dependent upon type I NKT cells. Thus liver injury is significantly inhibited in Jα18−/− mice deficient in type I NKT cells as well as following their inactivation by sulfatide-mediated activation of type II NKT cells. Furthermore we have identified a novel pathway involving all-trans retinoic acid (ATRA) and its receptor RARγ signaling that inhibits type I NKT cells and consequently ALD. A semi-quantitative PCR analysis of hepatic gene expression of some of the key proinflammatory molecules shared in human disease indicated that their upregulation in ALD is dependent upon type I NKT cells. Type I but not type II NKT cells become activated following alcohol feeding. Type I NKT cells-induced inflammation and neutrophil recruitment results in liver tissue damage while type II NKT cells protect from injury in ALD. Inhibition of type I NKT cells by retinoids or by sulfatide prevents ALD. Since the CD1d pathway is highly conserved between mice and humans, NKT cell subsets might be targeted for potential therapeutic intervention in ALD.
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DOI：
10.1002/hep.22470
发表时间：
2008-10
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Hritz I;Mandrekar P;Velayudham A;Catalano D;Dolganiuc A;Kodys K;Kurt-Jones E;Szabo G
通讯作者：
Szabo G
影响因子：
2.2
作者：
Kinjo, Yuki;Kitano, Naoki;Kronenberg, Mitchell
通讯作者：
Kronenberg, Mitchell
影响因子：
25.7
作者：
Ishikawa, Sachiko;Ikejima, Kenichi;Watanabe, Sumio
通讯作者：
Watanabe, Sumio
影响因子：
15.9
作者：
Halder, Ramesh C.;Aguilera, Carlos;Kumar, Vipin
通讯作者：
Kumar, Vipin
不变的天然杀手T细胞识别微生物危险信号引起的脂质自抗原。
影响因子：
30.5
作者：
Brennan, Patrick J.;Tatituri, Raju V. V.;Brigl, Manfred;Kim, Edy Y.;Tuli, Amit;Sanderson, Joseph P.;Gadola, Stephan D.;Hsu, Fong-Fu;Besra, Gurdyal S.;Brenner, Michael B.
通讯作者：
Brenner, Michael B.