Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis.

The IL-23/IL-17 pathway is implicated in autoimmune diseases, particularly psoriasis, where biologics targeting IL-23 and IL-17 have shown significant clinical efficacy. Retinoid-related orphan nuclear receptor gamma t (RORγt) is required for Th17 differentiation and IL-17 production in adaptive and...

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Autores: Xue, Xiaohua, Soroosh, Pejman, De Leon-Tabaldo, Aimee, Luna-Roman, Rosa, Sablad, Marciano, Rozenkrants, Natasha, Yu, Jingxue, Castro, Glenda, Banie, Homayon, Fung-Leung, Wai-Ping, Santamaria Babí, Luis F., Schlueter, Thomas, Albers, Michael, Leonard, Kristi, Budelsky, Alison L., Fourie, Anne M.
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/116509
Acesso em linha:https://hdl.handle.net/2445/116509
Access Level:acceso abierto
Palavra-chave:Artritis
Proteïnes
Psoriasi
Farmacologia
Arthritis
Proteins
Psoriasis
Pharmacology
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spelling Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis.Xue, XiaohuaSoroosh, PejmanDe Leon-Tabaldo, AimeeLuna-Roman, RosaSablad, MarcianoRozenkrants, NatashaYu, JingxueCastro, GlendaBanie, HomayonFung-Leung, Wai-PingSantamaria Babí, Luis F.Schlueter, ThomasAlbers, MichaelLeonard, KristiBudelsky, Alison L.Fourie, Anne M.ArtritisProteïnesPsoriasiFarmacologiaArthritisProteinsPsoriasisPharmacologyThe IL-23/IL-17 pathway is implicated in autoimmune diseases, particularly psoriasis, where biologics targeting IL-23 and IL-17 have shown significant clinical efficacy. Retinoid-related orphan nuclear receptor gamma t (RORγt) is required for Th17 differentiation and IL-17 production in adaptive and innate immune cells. We identified JNJ-54271074, a potent and highly-selective RORγt inverse agonist, which dose-dependently inhibited RORγt-driven transcription, decreased co-activator binding and promoted interaction with co-repressor protein. This compound selectively blocked Th17 differentiation, significantly reduced IL-17A production from memory T cells, and decreased IL-17A- and IL-22-producing human and murine γδ and NKT cells. In a murine collagen-induced arthritis model, JNJ-54271074 dose-dependently suppressed joint inflammation. Furthermore, JNJ-54271074 suppressed IL-17A production in human PBMC from rheumatoid arthritis patients. RORγt-deficient mice showed decreased IL-23-induced psoriasis-like skin inflammation and cytokine gene expression, consistent with dose-dependent inhibition in wild-type mice through oral dosing of JNJ-54271074. In a translational model of human psoriatic epidermal cells and skin-homing T cells, JNJ-54271074 selectively inhibited streptococcus extract-induced IL-17A and IL-17F. JNJ-54271074 is thus a potent, selective RORγt modulator with therapeutic potential in IL-23/IL-17 mediated autoimmune diseases.Nature Publishing Group2016info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/116509Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/srep37977Scientific Reports, 2016, vol. 6, p. 37977https://doi.org/10.1038/srep37977cc-by (c) Xue et al., 2016http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1165092026-05-27T06:46:51Z
dc.title.none.fl_str_mv Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis.
title Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis.
spellingShingle Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis.
Xue, Xiaohua
Artritis
Proteïnes
Psoriasi
Farmacologia
Arthritis
Proteins
Psoriasis
Pharmacology
title_short Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis.
title_full Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis.
title_fullStr Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis.
title_full_unstemmed Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis.
title_sort Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis.
dc.creator.none.fl_str_mv Xue, Xiaohua
Soroosh, Pejman
De Leon-Tabaldo, Aimee
Luna-Roman, Rosa
Sablad, Marciano
Rozenkrants, Natasha
Yu, Jingxue
Castro, Glenda
Banie, Homayon
Fung-Leung, Wai-Ping
Santamaria Babí, Luis F.
Schlueter, Thomas
Albers, Michael
Leonard, Kristi
Budelsky, Alison L.
Fourie, Anne M.
author Xue, Xiaohua
author_facet Xue, Xiaohua
Soroosh, Pejman
De Leon-Tabaldo, Aimee
Luna-Roman, Rosa
Sablad, Marciano
Rozenkrants, Natasha
Yu, Jingxue
Castro, Glenda
Banie, Homayon
Fung-Leung, Wai-Ping
Santamaria Babí, Luis F.
Schlueter, Thomas
Albers, Michael
Leonard, Kristi
Budelsky, Alison L.
Fourie, Anne M.
author_role author
author2 Soroosh, Pejman
De Leon-Tabaldo, Aimee
Luna-Roman, Rosa
Sablad, Marciano
Rozenkrants, Natasha
Yu, Jingxue
Castro, Glenda
Banie, Homayon
Fung-Leung, Wai-Ping
Santamaria Babí, Luis F.
Schlueter, Thomas
Albers, Michael
Leonard, Kristi
Budelsky, Alison L.
Fourie, Anne M.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Artritis
Proteïnes
Psoriasi
Farmacologia
Arthritis
Proteins
Psoriasis
Pharmacology
topic Artritis
Proteïnes
Psoriasi
Farmacologia
Arthritis
Proteins
Psoriasis
Pharmacology
description The IL-23/IL-17 pathway is implicated in autoimmune diseases, particularly psoriasis, where biologics targeting IL-23 and IL-17 have shown significant clinical efficacy. Retinoid-related orphan nuclear receptor gamma t (RORγt) is required for Th17 differentiation and IL-17 production in adaptive and innate immune cells. We identified JNJ-54271074, a potent and highly-selective RORγt inverse agonist, which dose-dependently inhibited RORγt-driven transcription, decreased co-activator binding and promoted interaction with co-repressor protein. This compound selectively blocked Th17 differentiation, significantly reduced IL-17A production from memory T cells, and decreased IL-17A- and IL-22-producing human and murine γδ and NKT cells. In a murine collagen-induced arthritis model, JNJ-54271074 dose-dependently suppressed joint inflammation. Furthermore, JNJ-54271074 suppressed IL-17A production in human PBMC from rheumatoid arthritis patients. RORγt-deficient mice showed decreased IL-23-induced psoriasis-like skin inflammation and cytokine gene expression, consistent with dose-dependent inhibition in wild-type mice through oral dosing of JNJ-54271074. In a translational model of human psoriatic epidermal cells and skin-homing T cells, JNJ-54271074 selectively inhibited streptococcus extract-induced IL-17A and IL-17F. JNJ-54271074 is thus a potent, selective RORγt modulator with therapeutic potential in IL-23/IL-17 mediated autoimmune diseases.
publishDate 2016
dc.date.none.fl_str_mv 2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/116509
url https://hdl.handle.net/2445/116509
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/srep37977
Scientific Reports, 2016, vol. 6, p. 37977
https://doi.org/10.1038/srep37977
dc.rights.none.fl_str_mv cc-by (c) Xue et al., 2016
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Xue et al., 2016
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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