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

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 HadaschikStefan Wölfl

Research output: Contribution to journalArticle (Academic Journal)peer-review

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)10
JournalCommunications Biology
Volume3
DOIs
Publication statusPublished - 2020

Bibliographical note

© The Author(s) 2020.

Keywords

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors/genetics
  • Cell Survival/drug effects
  • Hep G2 Cells
  • Humans
  • Immunosuppression Therapy/methods
  • Male
  • Mice
  • Organogold Compounds/immunology
  • Receptors, Aryl Hydrocarbon/genetics
  • Signal Transduction/drug effects
  • Transforming Growth Factor beta1/genetics

Fingerprint

Dive into the research topics of 'NHC-gold compounds mediate immune suppression through induction of AHR-TGFβ1 signalling in vitro and in scurfy mice'. Together they form a unique fingerprint.

Cite this