NHC-gold compounds mediate immune suppression through induction of AHR-TGFβ1 signalling in vitro and in scurfy mice

Publication type:
Journal article
Metadata:
Autoren
  • Xinlai Cheng
  • Stefanie Haeberle
  • Iart Luca Shytaj
  • Rodrigo A Gama-Brambila
  • Jannick Theobald
  • Shahrouz Ghafoory
  • Jessica Woelker
  • Uttara Basu
  • Claudia Schmidt
  • Annika Timm
  • Katerina Taskova
  • Andrea S Bauer
  • Joerg Hoheisel
  • Nikolaos Tsopoulidis
  • Oliver T Fackler
  • Andrea Savarino
  • Miguel A Andrade-Navarro
  • Ingo Ott
  • Marina Lusic
  • Eva N Hadaschik
  • Stefan Woelfl
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000620073500001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1038/s42003-019-0716-8
eISSN
2399-3642
Externe Identifier
  • Clarivate Analytics Document Solution ID: QK0LO
Ausgabe der Veröffentlichung
1
Zeitschrift
COMMUNICATIONS BIOLOGY
Artikelnummer
ARTN 10
Datum der Veröffentlichung
2020
Status
Published
Titel
NHC-gold compounds mediate immune suppression through induction of AHR-TGFβ1 signalling in vitro and in scurfy mice
Sub types
  • Article
Ausgabe der Zeitschrift
3

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:title>Abstract</jats:title><jats:p>Gold compounds have a long history of use as immunosuppressants, but their precise mechanism of action is not completely understood. Using our recently developed liver-on-a-chip platform we now show that gold compounds containing planar<jats:italic>N</jats:italic>-heterocyclic carbene (NHC) ligands are potent ligands for the aryl hydrocarbon receptor (AHR). Further studies showed that the lead compound (MC3) activates TGFβ1 signaling and suppresses CD4<jats:sup>+</jats:sup>T-cell activation in vitro, in human and mouse T cells. Conversely, genetic knockdown or chemical inhibition of AHR activity or of TGFβ1-SMAD-mediated signaling offsets the MC3-mediated immunosuppression. In scurfy mice, a mouse model of human immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, MC3 treatment reduced autoimmune phenotypes and extended lifespan from 24 to 58 days. Our findings suggest that the immunosuppressive activity of gold compounds can be improved by introducing planar NHC ligands to activate the AHR-associated immunosuppressive pathway, thus expanding their potential clinical application for autoimmune diseases.</jats:p>
Autoren
  • Xinlai Cheng
  • Stefanie Haeberle
  • Iart Luca Shytaj
  • Rodrigo A Gama-Brambila
  • Jannick Theobald
  • Shahrouz Ghafoory
  • Jessica Wölker
  • Uttara Basu
  • Claudia Schmidt
  • Annika Timm
  • Katerina Taškova
  • Andrea S Bauer
  • Jörg Hoheisel
  • Nikolaos Tsopoulidis
  • Oliver T Fackler
  • Andrea Savarino
  • Miguel A Andrade-Navarro
  • Ingo Ott
  • Marina Lusic
  • Eva N Hadaschik
  • Stefan Wölfl
DOI
10.1038/s42003-019-0716-8
eISSN
2399-3642
Ausgabe der Veröffentlichung
1
Zeitschrift
Communications Biology
Sprache
en
Artikelnummer
10
Online publication date
2020
Status
Published online
Herausgeber
Springer Science and Business Media LLC
Herausgeber URL
http://dx.doi.org/10.1038/s42003-019-0716-8
Datum der Datenerfassung
2023
Titel
NHC-gold compounds mediate immune suppression through induction of AHR-TGFβ1 signalling in vitro and in scurfy mice
Ausgabe der Zeitschrift
3

Data source: Crossref

Abstract
Gold compounds have a long history of use as immunosuppressants, but their precise mechanism of action is not completely understood. Using our recently developed liver-on-a-chip platform we now show that gold compounds containing planar <i>N</i>-heterocyclic carbene (NHC) ligands are potent ligands for the aryl hydrocarbon receptor (AHR). Further studies showed that the lead compound (MC3) activates TGFβ1 signaling and suppresses CD4<sup>+</sup> T-cell activation in vitro, in human and mouse T cells. Conversely, genetic knockdown or chemical inhibition of AHR activity or of TGFβ1-SMAD-mediated signaling offsets the MC3-mediated immunosuppression. In scurfy mice, a mouse model of human immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, MC3 treatment reduced autoimmune phenotypes and extended lifespan from 24 to 58 days. Our findings suggest that the immunosuppressive activity of gold compounds can be improved by introducing planar NHC ligands to activate the AHR-associated immunosuppressive pathway, thus expanding their potential clinical application for autoimmune diseases.
Addresses
  • 1Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
Autoren
  • Xinlai Cheng
  • Stefanie Haeberle
  • Iart Luca Shytaj
  • Rodrigo A Gama-Brambila
  • Jannick Theobald
  • Shahrouz Ghafoory
  • Jessica Wölker
  • Uttara Basu
  • Claudia Schmidt
  • Annika Timm
  • Katerina Taškova
  • Andrea S Bauer
  • Jörg Hoheisel
  • Nikolaos Tsopoulidis
  • Oliver T Fackler
  • Andrea Savarino
  • Miguel A Andrade-Navarro
  • Ingo Ott
  • Marina Lusic
  • Eva N Hadaschik
  • Stefan Wölfl
DOI
10.1038/s42003-019-0716-8
eISSN
2399-3642
Externe Identifier
  • PubMed Identifier: 31909202
  • PubMed Central ID: PMC6941985
Funding acknowledgements
  • Deutsche Forschungsgemeinschaft: TRR-156/C04
  • Bundesministerium für Bildung und Forschung: FKZ 031A303
  • Deutsche Forschungsgemeinschaft: CH 1690/2-1
Open access
true
ISSN
2399-3642
Zeitschrift
Communications biology
Schlüsselwörter
  • Animals
  • Humans
  • Mice
  • Receptors, Aryl Hydrocarbon
  • Signal Transduction
  • Cell Survival
  • Male
  • Organogold Compounds
  • Basic Helix-Loop-Helix Transcription Factors
  • Transforming Growth Factor beta1
  • Hep G2 Cells
  • Immunosuppression Therapy
Sprache
eng
Medium
Electronic-eCollection
Online publication date
2020
Open access status
Open Access
Paginierung
10
Datum der Veröffentlichung
2020
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2020
Titel
NHC-gold compounds mediate immune suppression through induction of AHR-TGFβ1 signalling in vitro and in scurfy mice.
Sub types
  • Research Support, Non-U.S. Gov't
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
3

Files

https://www.nature.com/articles/s42003-019-0716-8.pdf https://europepmc.org/articles/PMC6941985?pdf=render

Data source: Europe PubMed Central

Abstract
Gold compounds have a long history of use as immunosuppressants, but their precise mechanism of action is not completely understood. Using our recently developed liver-on-a-chip platform we now show that gold compounds containing planar N-heterocyclic carbene (NHC) ligands are potent ligands for the aryl hydrocarbon receptor (AHR). Further studies showed that the lead compound (MC3) activates TGFβ1 signaling and suppresses CD4+ T-cell activation in vitro, in human and mouse T cells. Conversely, genetic knockdown or chemical inhibition of AHR activity or of TGFβ1-SMAD-mediated signaling offsets the MC3-mediated immunosuppression. In scurfy mice, a mouse model of human immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, MC3 treatment reduced autoimmune phenotypes and extended lifespan from 24 to 58 days. Our findings suggest that the immunosuppressive activity of gold compounds can be improved by introducing planar NHC ligands to activate the AHR-associated immunosuppressive pathway, thus expanding their potential clinical application for autoimmune diseases.
Date of acceptance
2019
Autoren
  • Xinlai Cheng
  • Stefanie Haeberle
  • Iart Luca Shytaj
  • Rodrigo A Gama-Brambila
  • Jannick Theobald
  • Shahrouz Ghafoory
  • Jessica Wölker
  • Uttara Basu
  • Claudia Schmidt
  • Annika Timm
  • Katerina Taškova
  • Andrea S Bauer
  • Jörg Hoheisel
  • Nikolaos Tsopoulidis
  • Oliver T Fackler
  • Andrea Savarino
  • Miguel A Andrade-Navarro
  • Ingo Ott
  • Marina Lusic
  • Eva N Hadaschik
  • Stefan Wölfl
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/31909202
DOI
10.1038/s42003-019-0716-8
eISSN
2399-3642
Externe Identifier
  • PubMed Central ID: PMC6941985
Zeitschrift
Commun Biol
Schlüsselwörter
  • Bioinorganic chemistry
  • Immunosuppression
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Survival
  • Hep G2 Cells
  • Humans
  • Immunosuppression Therapy
  • Male
  • Mice
  • Organogold Compounds
  • Receptors, Aryl Hydrocarbon
  • Signal Transduction
  • Transforming Growth Factor beta1
Sprache
eng
Country
England
Paginierung
10
PII
716
Datum der Veröffentlichung
2020
Status
Published online
Datum, an dem der Datensatz öffentlich gemacht wurde
2021
Titel
NHC-gold compounds mediate immune suppression through induction of AHR-TGFβ1 signalling in vitro and in scurfy mice.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
3

Data source: PubMed

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