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Antagonizing Retinoic acid-related-orphan receptor gamma Activity Blocks the T Helper 17/Interleukin-17 Pathway Leading to Attenuated Pro-inflammatory Human Keratinocyte and Skin Responses

Ecoeur, Florence and Weiss, Jessica and Kaupmann, Klemens and Hintermann, Samuel and Orain, David and Guntermann, Christine (2019) Antagonizing Retinoic acid-related-orphan receptor gamma Activity Blocks the T Helper 17/Interleukin-17 Pathway Leading to Attenuated Pro-inflammatory Human Keratinocyte and Skin Responses. Frontiers in Immunology, 10 (Front.).

Abstract

The nuclear hormone receptor retinoic acid receptor-related-orphan-receptor-gamma
t (RORgt) is the key transcription factor required for Th17 cell differentiation and for
production of IL-17 family cytokines by innate and adaptive immune cells. Dysregulated
Th17 immune responses have been associated with the pathogenesis of several
inflammatory and autoimmune diseases such as psoriasis, psoriatic arthritis, and
ankylosing spondylitis. In this article, we describe the in vitro pharmacology of a potent
and selective low molecular weight RORgt inhibitor identified after a structure-based
hit-to-lead optimization effort. The compound interfered with co-activator binding to
the RORgt ligand binding domain and impaired the transcriptional activity of RORgt
as evidenced by blocked IL-17A secretion and RORE-mediated transactivation of
a luciferase reporter gene. The inhibitor effectively reduced IL-17A production by
human naive and memory T-cells and attenuated transcription of pro-inflammatory
Th17 signature genes, such as IL17F, IL22, IL26, IL23R, and CCR6. The compound
selectively suppressed the Th17/IL-17 pathway and did not interfere with polarization
of other T helper cell lineages. Furthermore, the inhibitor was selective for RORgt and
did not modify the transcriptional activity of the closely related family members RORa
and RORb. Using human keratinocytes cultured with supernatants from compound
treated Th17 cells we showed that pharmacological inhibition of RORgt translated to
suppressed IL-17-regulated gene expression in keratinocyte cell cultures. Furthermore,
in ex vivo immersion skin cultures our RORgt inhibitor suppressed IL-17A production
by Th17-skewed skin resident cells which correlated with reduced human b defensin 2
expression in the skin. Our data suggests that inhibiting RORgt transcriptional activity by
a low molecular weight inhibitor may hold utility for the treatment of Th17/IL-17-mediated
skin pathologies.

Item Type: Article
Date Deposited: 09 Apr 2019 00:45
Last Modified: 09 Apr 2019 00:45
URI: https://oak.novartis.com/id/eprint/38243

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