Invariant NKT cells promote alcohol-induced steatohepatitis through interleukin-1β in mice
Invariant NKT cells promote alcohol-induced steatohepatitis through interleukin-1β in mice
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DOI：
10.1016/j.jhep.2014.12.027
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发表时间：
2015-06-01
影响因子：
25.7
通讯作者：
Tian, Zhigang
中科院分区：
文献类型：
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作者：
Cui, Kele;Yan, Guoxiu;Tian, Zhigang
背景和目标：据报道，酒精消耗激活库普弗细胞中的NLRP 3炎性体，导致酒精性肝损伤中成熟的白细胞介素（IL）-1 β释放;然而，IL-1 β如何促进肝损伤仍不清楚。方法：我们通过使用慢性加单次酒精消耗的小鼠模型研究了IL-1 β在酒精性脂肪性肝炎中的作用。在这里，肝脏脂肪变性伴随着显著增加的不变的自然杀伤T（iNKT）细胞数量和激活，iNKT缺陷的J α 18（-/）-小鼠发生较少的酒精诱导的脂肪变性，肝脏炎症和中性粒细胞浸润减少。肝iNKT蓄积需要枯否细胞和IL-1 β，因为用重组IL-1受体拮抗剂（IL-1 Ra）阻断IL-1 β信号传导，通过氯膦酸盐脂质体消耗枯否细胞，或通过纳米颗粒包封的siRNA特异性沉默枯否细胞中的IL-1 β，导致抑制肝iNKT细胞蓄积和活化，以及改善酒精性脂肪肝。此外，肝细胞中的IL-1b过表达足以补偿枯否细胞耗竭。成熟IL-1 β的基因和蛋白表达增加与来自乙醇暴露的野生型小鼠的Kupffer细胞中NLRP 3炎性体组分NLRP 3、ASC和裂解的半胱天冬酶-1的表达升高相关。NLRP 3缺乏导致酒精性脂肪变性的衰减，类似于枯否细胞耗竭，几乎没有肝NKT cells.Conclusions：酒精暴露后枯否细胞衍生的IL-1 β触发NLRP 3激活，招募和激活肝iNKT细胞，随后促进肝脏炎症和中性粒细胞浸润，并诱导酒精性肝损伤。(C)2015年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: It was reported that alcohol consumption activated the NLRP3 inflammasome in Kupffer cells, leading to mature interleukin (IL)-1 beta release in alcoholic liver injury; however, how IL-1 beta promotes liver injury remains unclear.Methods: We investigated the role of IL-1 beta in alcoholic steatohepatitis by using a chronic plus single-binge ethanol consumption mouse model.Results: Here, liver steatosis was accompanied by notably increased invariant natural killer T (iNKT) cell numbers and activation, and iNKT-deficient J alpha 18(-/)-mice developed less alcohol-induced steatosis, with reduced liver inflammation and neutrophil infiltration. Kupffer cells and IL-1 beta were required for the hepatic iNKT accumulation, as either blocking IL-1 beta signaling with a recombinant IL-1 receptor antagonist (IL-1Ra), depleting Kupffer cells by clodronate liposomes, or specifically silencing IL-1 beta in Kupffer cells by nanoparticle-encapsulated siRNA, resulted in inhibited hepatic iNKT cell accumulation and activation, as well as amelioration of alcoholic fatty liver. In addition, IL-1b overexpression in hepatocytes was sufficient to compensate for Kupffer cell depletion. Increased gene and protein expression of mature IL-1 beta correlated with elevated expression of the NLRP3 inflammasome components NLRP3, ASC, and cleaved caspase-1 in Kupffer cells from ethanol-exposed wild-type mice. NLRP3 deficiency led to the attenuation of alcoholic steatosis, similarly as Kupffer cell depletion, almost without hepatic NKT cells.Conclusions: After alcohol-exposure Kupffer cell-derived IL-1 beta triggered by NLRP3 activation, recruits and activates hepatic iNKT cells, subsequently promoting liver inflammation and neutrophil infiltration, and inducing alcoholic liver injury. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.