In vivo regulation of gene expression and T helper type 17 differentiation by RORγt inverse agonists. Issue 3 (3rd April 2015)

• Record Type: Journal Article
• Authors: Skepner, Jill; Trocha, Mark; Ramesh, Radha; Qu, Xiaoyan A.; Schmidt, Darby; Baloglu, Erkan; Lobera, Mercedes; Davis, Scott; Nolan, Michael A.; Carlson, Thaddeus J.; Hill, Jonathan; Ghosh, Shomir; Sundrud, Mark S.; Yang, Jianfei
• Is Part Of: Immunology. Volume 145:Issue 3(2015:Jul.)
• Page Start: 347
• Page End: 356
• Publication Date: 2015-04-03
• Subjects: Immunology -- Periodicals
• DOI: 10.1111/imm.12444
• Languages: English
• ISSNs: 0019-2805

Abstract

<abstract abstract-type="main" id="imm12444-abs-0001"> <title>Summary</title> <p>The orphan nuclear receptor, retinoic acid receptor‐related orphan nuclear receptor <italic>γ</italic>t (ROR<italic>γ</italic>t), is required for the development and pathogenic function of interleukin‐17A‐secreting CD4<sup>+</sup> T helper type 17 (Th17) cells. Whereas small molecule ROR<italic>γ</italic>t antagonists impair Th17 cell development and attenuate autoimmune inflammation <italic>in vivo</italic>, the broader effects of these inhibitors on ROR<italic>γ</italic>t‐dependent gene expression <italic>in vivo</italic> has yet to be characterized. We show that the ROR<italic>γ</italic>t inverse agonist TMP778 acts potently and selectively to block mouse Th17 cell differentiation <italic>in vitro</italic> and to impair Th17 cell development <italic>in vivo</italic> upon immunization with the myelin antigen MOG<sub>35–55</sub> plus complete Freund's adjuvant. Importantly, we show that TMP778 acts <italic>in vivo</italic> to repress the expression of more than 150 genes, most of which fall outside the canonical Th17 transcriptional signature and are linked to a variety of inflammatory pathologies in humans. Interestingly, more than 30 genes are related with SMAD3, a transcription factor involved in the Th17 cell differentiation. These results reveal novel disease‐associated genes regulated by ROR<italic>γ</italic>t during inflammation <italic>in vivo</italic>, and provide an early read on potential disease indications and safety concerns associated with pharmacological targeting of ROR<italic>γ</italic>t.</p> </abstract>