Pharmacological inhibition of ROR?t suppresses the Th17 pathway and alleviates arthritis in vivo.

ABSTRACT: Retinoic acid receptor-related-orphan-receptor-C (ROR?t) is the key transcription factor that is driving the differentiation of IL-17 producing T-helper 17 (Th17) cells that are implicated in the pathology of various autoimmune and inflammatory diseases. Based on the importance of ROR?t in promoting Th17-driven pathology, there is considerable interest to develop low-molecular-weight compounds with the aim of inhibiting the transcriptional activity of this nuclear hormone receptor. In this article, we describe the in vitro and in vivo pharmacology of a potent and selective small-molecular-weight ROR?t inverse agonist. The compound binds to the ligand binding domain (LBD) of ROR?t leading to displacement of a co-activator peptide. We show for the first time that a ROR?t inverse agonist down-regulates permissive histone H3 acetylation and methylation at the IL17A and IL23R promoter regions, thereby providing insight into the transcriptional inhibition of ROR?t-dependent genes. Consistent with this, the compound effectively reduced IL-17A production by polarized human T-cells and ??T-cells and attenuated transcription of ROR?t target genes. The inhibitor showed good in vivo efficacy in an antigen-induced arthritis model in rats and reduced the frequencies of IL-17A producing cells in ex vivo recall assays. In summary, we demonstrate that inhibiting ROR?t by a low-molecular-weight inhibitor results in efficient and selective blockade of the pro-inflammatory Th17/IL-17A pathway making it an attractive target for Th17-mediated disorders.

SUBMITTER: Guendisch U 

PROVIDER: S-EPMC5695821 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature