File Download
  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Down-regulation of STAT3 enhanced chemokine expression and neutrophil recruitment in biliary atresia

TitleDown-regulation of STAT3 enhanced chemokine expression and neutrophil recruitment in biliary atresia
Authors
KeywordsBiliary atresia
Neutrophil chemoattractants
STAT3
Issue Date2021
PublisherPortland Press Ltd. The Journal's web site is located at http://www.clinsci.org/
Citation
Clinical Science, 2021, v. 135 n. 7, p. 865-884 How to Cite?
AbstractBiliary atresia (BA) is an immune-related disorder and signal transducer and activator of transcription 3 (STAT3) is a key signalling molecule in inflammation. The present study was designed to clarify the function of STAT3 in BA. STAT3 expression was examined in patients and a mouse BA model in which STAT3 levels were further altered with a specific inhibitor or activator. Neutrophil accumulation and the levels of the neutrophil chemoattractants (C–X–C motif) ligand 1 (CXCL1) and IL-8 were determined. The effects of STAT3 inhibition on IL-8 expression were examined in human biliary epithelial cell (BEC) cultures. Functional changes in liver STAT3+ neutrophils in the mouse model were analysed with 10× single cell RNA-seq methods. Results showed STAT3 and p-STAT3 expression was reduced in BA liver tissue compared with control samples. Administration of a STAT3 inhibitor increased jaundice and mortality and reduced body weight in BA mice. In contrast, the STAT3 activator ameliorated BA symptoms. Extensive neutrophil accumulation together with CXCL1 up-regulation, both of which were suppressed by an anti-CXCL1 antibody, were observed in the STAT3 inhibitor-treated group. Recombinant IL-8 administration increased disease severity in BA mice, and the STAT3 activator had the reverse effect. Inhibiting STAT3 increased apoptosis of human BECs together with up-regulated IL-8 expression. RNA-seq analysis revealed reduced the numbers of STAT3 expressing neutrophil in BA which was accompanied by marked enhanced interferon-related antiviral activities. In conclusion, STAT3 reduction, enhanced IL-8 and CXCL1 expression and promoted the accumulation of interferon-responsive neutrophils resulting in BEC damage in BA.
Persistent Identifierhttp://hdl.handle.net/10722/299321
ISSN
2023 Impact Factor: 6.7
2023 SCImago Journal Rankings: 1.565
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorFu, M-
dc.contributor.authorTan, L-
dc.contributor.authorLin, Z-
dc.contributor.authorLui, VCH-
dc.contributor.authorTam, PKH-
dc.contributor.authorLamb, JR-
dc.contributor.authorZhang, Y-
dc.contributor.authorXia, H-
dc.contributor.authorZhang, R-
dc.contributor.authorChen, Y-
dc.date.accessioned2021-05-10T07:00:08Z-
dc.date.available2021-05-10T07:00:08Z-
dc.date.issued2021-
dc.identifier.citationClinical Science, 2021, v. 135 n. 7, p. 865-884-
dc.identifier.issn0143-5221-
dc.identifier.urihttp://hdl.handle.net/10722/299321-
dc.description.abstractBiliary atresia (BA) is an immune-related disorder and signal transducer and activator of transcription 3 (STAT3) is a key signalling molecule in inflammation. The present study was designed to clarify the function of STAT3 in BA. STAT3 expression was examined in patients and a mouse BA model in which STAT3 levels were further altered with a specific inhibitor or activator. Neutrophil accumulation and the levels of the neutrophil chemoattractants (C–X–C motif) ligand 1 (CXCL1) and IL-8 were determined. The effects of STAT3 inhibition on IL-8 expression were examined in human biliary epithelial cell (BEC) cultures. Functional changes in liver STAT3+ neutrophils in the mouse model were analysed with 10× single cell RNA-seq methods. Results showed STAT3 and p-STAT3 expression was reduced in BA liver tissue compared with control samples. Administration of a STAT3 inhibitor increased jaundice and mortality and reduced body weight in BA mice. In contrast, the STAT3 activator ameliorated BA symptoms. Extensive neutrophil accumulation together with CXCL1 up-regulation, both of which were suppressed by an anti-CXCL1 antibody, were observed in the STAT3 inhibitor-treated group. Recombinant IL-8 administration increased disease severity in BA mice, and the STAT3 activator had the reverse effect. Inhibiting STAT3 increased apoptosis of human BECs together with up-regulated IL-8 expression. RNA-seq analysis revealed reduced the numbers of STAT3 expressing neutrophil in BA which was accompanied by marked enhanced interferon-related antiviral activities. In conclusion, STAT3 reduction, enhanced IL-8 and CXCL1 expression and promoted the accumulation of interferon-responsive neutrophils resulting in BEC damage in BA.-
dc.languageeng-
dc.publisherPortland Press Ltd. The Journal's web site is located at http://www.clinsci.org/-
dc.relation.ispartofClinical Science-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectBiliary atresia-
dc.subjectNeutrophil chemoattractants-
dc.subjectSTAT3-
dc.titleDown-regulation of STAT3 enhanced chemokine expression and neutrophil recruitment in biliary atresia-
dc.typeArticle-
dc.identifier.emailLui, VCH: vchlui@hku.hk-
dc.identifier.emailTam, PKH: paultam@hku.hk-
dc.identifier.emailChen, Y: ychenc@hku.hk-
dc.identifier.authorityLui, VCH=rp00363-
dc.identifier.authorityTam, PKH=rp00060-
dc.identifier.authorityChen, Y=rp01318-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1042/CS20201366-
dc.identifier.pmid33769466-
dc.identifier.pmcidPMC8035628-
dc.identifier.scopuseid_2-s2.0-85104209845-
dc.identifier.hkuros322359-
dc.identifier.volume135-
dc.identifier.issue7-
dc.identifier.spage865-
dc.identifier.epage884-
dc.identifier.isiWOS:000648650800001-
dc.publisher.placeUnited Kingdom-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats