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

TitleNLRP3 inflammasome induced liver graft injury through activation of telomere-independent RAP1/KC axis
Authors
KeywordsInflammasomes
KC
Liver transplantation
Neutrophil
RAP1
Issue Date2017
PublisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130
Citation
Journal of Pathology, 2017, v. 242 n. 3, p. 284-296 How to Cite?
AbstractAcute-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.
Persistent Identifierhttp://hdl.handle.net/10722/241314
ISSN
2017 Impact Factor: 6.253
2015 SCImago Journal Rankings: 4.176
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLiu, H-
dc.contributor.authorLo, CM-
dc.contributor.authorYeung, WH-
dc.contributor.authorLi, C-
dc.contributor.authorLiu, X-
dc.contributor.authorQi, X-
dc.contributor.authorNg, KTP-
dc.contributor.authorLIU, J-
dc.contributor.authorMA, YY-
dc.contributor.authorLam, YF-
dc.contributor.authorLian, Q-
dc.contributor.authorChan, SC-
dc.contributor.authorMan, K-
dc.date.accessioned2017-06-05T08:02:19Z-
dc.date.available2017-06-05T08:02:19Z-
dc.date.issued2017-
dc.identifier.citationJournal of Pathology, 2017, v. 242 n. 3, p. 284-296-
dc.identifier.issn0022-3417-
dc.identifier.urihttp://hdl.handle.net/10722/241314-
dc.description.abstractAcute-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.-
dc.languageeng-
dc.publisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130-
dc.relation.ispartofJournal of Pathology-
dc.rightsJournal of Pathology. Copyright © John Wiley & Sons.-
dc.rightsPreprint: This is the pre-peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. Postprint: This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. Special Statement for Preprint only Before publication: 'This is a preprint of an article accepted for publication in [The Journal of Pathology] Copyright © ([year]) ([Pathological Society of Great Britain and Ireland])'. After publication: the preprint notice should be amended to follows: 'This is a preprint of an article published in [include the complete citation information for the final version of the Contribution as published in the print edition of the Journal]' For Cochrane Library/ Cochrane Database of Systematic Reviews, add statement & acknowledgement : ‘This review is published as a Cochrane Review in the Cochrane Database of Systematic Reviews 20XX, Issue X. Cochrane Reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and the Cochrane Database of Systematic Reviews should be consulted for the most recent version of the Review.’ Please include reference to the Review and hyperlink to the original version using the following format e.g. Authors. Title of Review. Cochrane Database of Systematic Reviews 20XX, Issue #. Art. No.: CD00XXXX. DOI: 10.1002/14651858.CD00XXXX (insert persistent link to the article by using the URL: http://dx.doi.org/10.1002/14651858.CD00XXXX) (This statement should refer to the most recent issue of the Cochrane Database of Systematic Reviews in which the Review published.)-
dc.subjectInflammasomes-
dc.subjectKC-
dc.subjectLiver transplantation-
dc.subjectNeutrophil-
dc.subjectRAP1-
dc.titleNLRP3 inflammasome induced liver graft injury through activation of telomere-independent RAP1/KC axis-
dc.typeArticle-
dc.identifier.emailLiu, H: liuhui25@hku.hk-
dc.identifier.emailLo, CM: chungmlo@hkucc.hku.hk-
dc.identifier.emailYeung, WH: why21@hku.hk-
dc.identifier.emailLiu, X: liuxb301@hku.hk-
dc.identifier.emailQi, X: qixiang515@connect.hku.hk-
dc.identifier.emailNg, KTP: ledodes@hku.hk-
dc.identifier.emailLian, Q: qzlian@hkucc.hku.hk-
dc.identifier.emailChan, SC: chanlsc@hkucc.hku.hk-
dc.identifier.emailMan, K: kwanman@hku.hk-
dc.identifier.authorityLo, CM=rp00412-
dc.identifier.authorityNg, KTP=rp01720-
dc.identifier.authorityLian, Q=rp00267-
dc.identifier.authorityChan, SC=rp01568-
dc.identifier.authorityMan, K=rp00417-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/path.4901-
dc.identifier.pmid28378341-
dc.identifier.scopuseid_2-s2.0-85019222976-
dc.identifier.hkuros274735-
dc.identifier.volume242-
dc.identifier.issue3-
dc.identifier.spage284-
dc.identifier.epage296-
dc.identifier.isiWOS:000403455400004-
dc.publisher.placeUnited Kingdom-

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