NLRP3 inflammasome induced liver graft injury through activation of telomere-independent RAP1/KC axis

J Pathol. 2017 Jul;242(3):284-296. doi: 10.1002/path.4901. Epub 2017 May 15.

Abstract

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.

Keywords: KC; RAP1; inflammasomes; liver transplantation; neutrophil.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / etiology
  • Acute Lung Injury / metabolism
  • Adult
  • Aged
  • Animals
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Gene Knockdown Techniques
  • Hepatectomy / methods
  • Humans
  • Inflammasomes / metabolism*
  • Liver Transplantation*
  • Male
  • Mice, Inbred C57BL
  • Middle Aged
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Neutrophils / metabolism
  • Reperfusion Injury / metabolism
  • Telomere-Binding Proteins / metabolism
  • Up-Regulation / physiology
  • Young Adult
  • rap1 GTP-Binding Proteins / deficiency
  • rap1 GTP-Binding Proteins / metabolism

Substances

  • Cytokines
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • TERF2IP protein, human
  • Telomere-Binding Proteins
  • Rap1 protein, mouse
  • rap1 GTP-Binding Proteins