The MS Remyelinating Drug Bexarotene (an RXR Agonist) Promotes Induction of Human Tregs and Suppresses Th17 Differentiation In Vitro.

Christopher M Gaunt,Hani S Mousa,Ruairi J Mackenzie,Joanne L Jones,Zoya Georgieva,Nicholas Cunniffe,J William Brown,Daniel B Rainbow,Alasdair J Coles,Lorna B Jarvis

doi:10.3389/fimmu.2021.712241

Christopher M Gaunt, Hani S Mousa + Show 8 more

Open Access

https://doi.org/10.3389/fimmu.2021.712241

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Abstract

The retinoid X receptor agonist bexarotene promotes remyelination in patients with multiple sclerosis. Murine studies have also demonstrated that RXR agonists have anti-inflammatory effects by enhancing the ability of all-trans-retinoic acid (atRA) to promote T-regulatory cell (Treg) induction and reduce Th17 differentiation in vitro. By stimulating human naïve CD4 T-cells in the presence of Treg or Th17 skewing cytokines, we show that bexarotene also tips the human Treg/Th17 axis in favor of Treg induction, but unlike murine cells this occurs independently of atRA and retinoic acid receptor signaling. Tregs induced in the presence of bexarotene express canonical markers of T-regulation and are functionally suppressive in vitro. Circulating Treg numbers did not increase in the blood of trial patients receiving bexarotene; we believe this is because Treg induction is likely to occur within tissues. These findings lend support to developing RXR agonists as treatments of autoimmune diseases, in particular multiple sclerosis.

Highlights

Bexarotene, a pan retinoid X receptor (RXR) agonist licensed for use in humans as a treatment of cutaneous T-cell lymphoma, has recently been shown to promote remyelination in multiple sclerosis (MS)
AtRA binds to the retinoic acid receptor (RAR) which is bound to DNA as a heterodimer with RXR in regions called retinoic acid response elements (RAREs)
In contrast to what was expected from murine studies, bexarotene alone was sufficient to increase Tregulatory cell (Treg) induction as measured by percent FOXP3 expression (Figure 1A, from 21.52% to 39.25% p=0.0038)

Summary

Introduction

Bexarotene, a pan retinoid X receptor (RXR) agonist licensed for use in humans as a treatment of cutaneous T-cell lymphoma, has recently been shown to promote remyelination in multiple sclerosis (MS). The CCMR-One clinical trial largely came about because of work done in rodents, which demonstrated that oligodendrocytes express RXR ( RXR-g) during active remyelination, and that remyelination can be promoted, in vitro and in vivo, following administration of RXR agonists [1]. Murine studies have demonstrated that RXR agonists can enhance the ability of all-trans-retinoic acid (atRA), the primary active metabolite of vitamin A, to promote Treg induction (iTregs), and reduce Th17 differentiation in vitro, following stimulation of naïve CD4 cells in the presence of TGF- b [2]. Binding of atRA to the RAR/RXR heterodimer leads to a conformational change, which in turn promotes down-stream transcription of hundreds of genes [3], including those involved in the induction of Tregs

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