NLRP3 inflammasome induced liver graft injury through activation of telomere-independent RAP1/KC axis.
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.
['Liu|Hui|H|', 'Lo|Chung Mau|CM|', 'Yeung|Oscar Wai Ho|OWH|', 'Li|Chang Xian|CX|', 'Liu|Xiao Bing|XB|', 'Qi|Xiang|X|', 'Ng|Kevin Tak Pan|KTP|', 'Liu|Jiang|J|', 'Ma|Yuen Yuen|YY|', 'Lam|Yin Fan|YF|', 'Lian|Qizhou|Q|', 'Chan|See Ching|SC|', 'Man|Kwan|K|0000-0001-5663-6866']
D055371:Acute Lung Injury D000328:Adult D000368:Aged D000818:Animals D016207:Cytokines D004195:Disease Models, Animal D005260:Female D055785:Gene Knockdown Techniques D006498:Hepatectomy D006801:Humans D058847:Inflammasomes D016031:Liver Transplantation D008297:Male D008810:Mice, Inbred C57BL D008875:Middle Aged D000071199:NLR Family, Pyrin Domain-Containing 3 Protein D009504:Neutrophils D015427:Reperfusion Injury D000089804:Shelterin Complex D034501:Telomere-Binding Proteins D015854:Up-Regulation D055815:Young Adult D020827:rap1 GTP-Binding Proteins
inflammasomes RAP1 KC liver transplantation neutrophil