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

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.

Aryl hydrocarbon receptor and TGF-β inducible early gene mediate a transcriptional axis modulating immune homeostasis in mosquitoes

“…TIEG has functional connections with TGFβ1 pathway in Drosophila and vertebrates [45, 49]. Recently, AhR-TGFβ1/Smad signaling has been shown to mediate immune suppression in scurfy mice, a mouse autoimmune model [46]. We hypothesize that AhR and TIEG form a transcriptional axis to mediate immune regulation and supported this hypothesis with three lines of evidence.…”

“…There are cross talks between AhR and TGF-β pathway in anti-inflammatory processes demonstrated in mammals [57][58][59]. A direct evidence of AhR/TGF-β/Smad pathway in an anti-inflammation context was demonstrated lately in scurfy mice, a mouse model of immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, in which ligand activated AhR-TGF-β/Smad signaling mediates autoimmune suppression [40,46]. The current findings that AhR signaling connects chemical sensing and immune regulation in mosquitoes warrant further study to elucidate the cross talk between xenobiotic defense and immune defense in insect level.…”

“…The orthologous gene in Drosophila is Cabut, which is involved in development, metabolism and growth control [42][43][44][45]. In vertebrates, AhR and TGF-β/Smad signaling are connected to mediate immune suppression to maintain immune homeostasis [46], and TIEG is involved in TGF-β/Smad signaling [47][48][49]. Based on this background information, we tested the hypothesis that TIEG is downstream of AhR, mediating the transcription of genes responsible for immune modulation.…”

Auranofin Attenuates Non-Alcoholic Fatty Liver Disease by Suppressing Lipid Accumulation and NLRP3 Inflammasome-Mediated Hepatic Inflammation In Vivo and In Vitro

“…Gold-based compounds have been used in a wide range of treatments for a long time, and among them, their role as a treatment for rheumatoid arthritis is the most representative [ 22 , 23 ]. These compounds are suggested for their immunosuppressive activity by inhibiting immune cell activation [ 24 , 25 ]. Auranofin is a gold-containing compound and an FDA-approved drug for the treatment of rheumatoid arthritis and has been studied for potential preventive applications in several other diseases, including cancer, neurodegenerative disorders, pathogenic infections, and inflammation [ 26 , 27 , 28 ].…”

Gold Metallodrugs to Target Coronavirus Proteins: Inhibitory Effects on the Spike‐ACE2 Interaction and on PLpro Protease Activity by Auranofin and Gold Organometallics**

“…[10] Here we report the resultso fapilot study,i nw hichw ei nvestigated the effects of Auranofin and selected experimental gold metallodrugs( see Figure1)o nt wo relevant coronavirus targets (spikep rotein, papain like protease, PLpro). Whereas Au-1, [11] Au-3 [12,13] and Au-5 [14] were selected from our previous workso no rganometallic gold metallodrugs, Au-2 and Au-4 have not been reported before and their synthesis and characterization are described here. Complexes Au-1 to Au-5 are organometallics containinge ither a N-heterocyclicc arbene (NHC) or an alkynyll igand.C omplexes of these types have demonstrated promising activities in af ast increasing number of recentr eports.…”