Liu Hui, Lo Chung Mau, Yeung Oscar Wai Ho, Li Chang Xian, Liu Xiao Bing, Qi Xiang, Ng Kevin Tak Pan, Liu Jiang, Ma Yuen Yuen, Lam Yin Fan, Lian Qizhou, Chan See Ching, Man Kwan
Department of Surgery, Faculty of Medicine, The University of Hong Kong, Hong Kong, PR China.
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, PR China.
J Pathol. 2017 Jul;242(3):284-296. doi: 10.1002/path.4901. Epub 2017 May 15.
Acute-phase inflammation plays a critical role in liver graft injury. Inflammasomes, multi-molecular complexes in the cytoplasm, are responsible for initiating inflammation. Here, we aimed to explore the role of inflammasomes in liver graft injury and further to investigate the regulatory mechanism. In a clinical liver transplant cohort, we found that intragraft expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes was significantly up-regulated post-transplantation. Importantly, overexpression of NLRP3 was strongly associated with poor liver function characterized by high levels of ALT, AST, and urea, as well as neutrophil infiltration after transplantation. The significant correlation between NLRP3 and IL-1β mRNA levels led us to focus on one of the associated upstream regulators, telomere-independent repressor activator protein 1 (RAP1), which was further proved to be co-localized with NLRP3 in neutrophils. In the liver of a mouse model (hepatic ischaemia/reperfusion and hepatectomy model) and isolated neutrophils from RAP1 mice, the expression levels of NLRP3 and keratinocyte chemoattractant (KC) were significantly down-regulated in contrast to those in wild types. The levels of ALT and AST, as well as the neutrophil infiltration, were also decreased by RAP1 deficiency. In our clinical validation, intragraft KC expression was associated with NLRP3 and co-localized with RAP1 in neutrophils. Furthermore, NLRP3 inflammasomes were up-regulated by recombinant KC in the isolated neutrophils and liver of the mouse model. Our data demonstrated that NLRP3 inflammasomes, activated by the RAP1/KC axis, played a critical role in initiating inflammation during the early stage of liver graft injury. Targeting RAP1/KC/NLRP3 inflammasomes may offer a new therapeutic strategy against liver graft injury. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
急性期炎症在肝移植损伤中起关键作用。炎性小体是细胞质中的多分子复合物，负责引发炎症。在此，我们旨在探讨炎性小体在肝移植损伤中的作用，并进一步研究其调控机制。在一个临床肝移植队列中，我们发现移植后核苷酸结合寡聚化结构域样受体家族含pyrin结构域3（NLRP3）炎性小体的移植物内表达显著上调。重要的是，NLRP3的过表达与以高水平谷丙转氨酶（ALT）、谷草转氨酶（AST）和尿素以及移植后中性粒细胞浸润为特征的肝功能不良密切相关。NLRP3与白细胞介素-1β（IL-1β）mRNA水平之间的显著相关性使我们关注其中一个相关的上游调节因子，即端粒非依赖性阻遏激活蛋白1（RAP1），进一步证明其在中性粒细胞中与NLRP3共定位。在小鼠模型（肝缺血/再灌注和肝切除模型）的肝脏以及来自RAP1基因敲除小鼠的分离中性粒细胞中，与野生型相比，NLRP3和角质形成细胞趋化因子（KC）的表达水平显著下调。RAP1缺乏也降低了ALT和AST水平以及中性粒细胞浸润。在我们的临床验证中，移植物内KC表达与NLRP3相关，且在中性粒细胞中与RAP1共定位。此外，在小鼠模型的分离中性粒细胞和肝脏中，重组KC使NLRP3炎性小体上调。我们的数据表明，由RAP1/KC轴激活的NLRP3炎性小体在肝移植损伤早期引发炎症中起关键作用。靶向RAP1/KC/NLRP3炎性小体可能为肝移植损伤提供一种新的治疗策略。版权所有© 2017英国和爱尔兰病理学会。由约翰·威利父子有限公司出版。
