The demethylase inhibitor GSK-J4 limits inflammatory colitis by promoting de novo synthesis of retinoic acid in dendritic cells

Abstract Dendritic cells (DCs) promote T-cell mediated tolerance to self-antigens and induce inflammation to innocuous-antigens. This dual potential makes DCs fundamental players in inflammatory disorders. Evidence from inflammatory colitis mouse models and inflammatory bowel diseases (IBD) patients...

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Autores principales:	Cristian Doñas, Jocelyn Neira, Francisco Osorio-Barrios, Macarena Carrasco, Dominique Fernández, Carolina Prado, Alejandra Loyola, Rodrigo Pacheco, Mario Rosemblatt
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/64dc632d8ccf474eadb8e5911839b251
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spelling	oai:doaj.org-article:64dc632d8ccf474eadb8e5911839b2512021-12-02T14:01:22ZThe demethylase inhibitor GSK-J4 limits inflammatory colitis by promoting de novo synthesis of retinoic acid in dendritic cells10.1038/s41598-020-79122-32045-2322https://doaj.org/article/64dc632d8ccf474eadb8e5911839b2512021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79122-3https://doaj.org/toc/2045-2322Abstract Dendritic cells (DCs) promote T-cell mediated tolerance to self-antigens and induce inflammation to innocuous-antigens. This dual potential makes DCs fundamental players in inflammatory disorders. Evidence from inflammatory colitis mouse models and inflammatory bowel diseases (IBD) patients indicated that gut inflammation in IBD is driven mainly by T-helper-1 (Th1) and Th17 cells, suggesting an essential role for DCs in the development of IBD. Here we show that GSK-J4, a selective inhibitor of the histone demethylase JMJD3/UTX, attenuated inflammatory colitis by reducing the inflammatory potential and increasing the tolerogenic features of DCs. Mechanistic analyses revealed that GSK-J4 increased activating epigenetic signals while reducing repressive marks in the promoter of retinaldehyde dehydrogenase isoforms 1 and 3 in DCs, enhancing the production of retinoic acid. This, in turn, has an impact on regulatory T cells (Treg) increasing their lineage stability and gut tropism as well as potentiating their suppressive activity. Our results open new avenues for the treatment of IBD patients.Cristian DoñasJocelyn NeiraFrancisco Osorio-BarriosMacarena CarrascoDominique FernándezCarolina PradoAlejandra LoyolaRodrigo PachecoMario RosemblattNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cristian Doñas Jocelyn Neira Francisco Osorio-Barrios Macarena Carrasco Dominique Fernández Carolina Prado Alejandra Loyola Rodrigo Pacheco Mario Rosemblatt The demethylase inhibitor GSK-J4 limits inflammatory colitis by promoting de novo synthesis of retinoic acid in dendritic cells
description	Abstract Dendritic cells (DCs) promote T-cell mediated tolerance to self-antigens and induce inflammation to innocuous-antigens. This dual potential makes DCs fundamental players in inflammatory disorders. Evidence from inflammatory colitis mouse models and inflammatory bowel diseases (IBD) patients indicated that gut inflammation in IBD is driven mainly by T-helper-1 (Th1) and Th17 cells, suggesting an essential role for DCs in the development of IBD. Here we show that GSK-J4, a selective inhibitor of the histone demethylase JMJD3/UTX, attenuated inflammatory colitis by reducing the inflammatory potential and increasing the tolerogenic features of DCs. Mechanistic analyses revealed that GSK-J4 increased activating epigenetic signals while reducing repressive marks in the promoter of retinaldehyde dehydrogenase isoforms 1 and 3 in DCs, enhancing the production of retinoic acid. This, in turn, has an impact on regulatory T cells (Treg) increasing their lineage stability and gut tropism as well as potentiating their suppressive activity. Our results open new avenues for the treatment of IBD patients.
format	article
author	Cristian Doñas Jocelyn Neira Francisco Osorio-Barrios Macarena Carrasco Dominique Fernández Carolina Prado Alejandra Loyola Rodrigo Pacheco Mario Rosemblatt
author_facet	Cristian Doñas Jocelyn Neira Francisco Osorio-Barrios Macarena Carrasco Dominique Fernández Carolina Prado Alejandra Loyola Rodrigo Pacheco Mario Rosemblatt
author_sort	Cristian Doñas
title	The demethylase inhibitor GSK-J4 limits inflammatory colitis by promoting de novo synthesis of retinoic acid in dendritic cells
title_short	The demethylase inhibitor GSK-J4 limits inflammatory colitis by promoting de novo synthesis of retinoic acid in dendritic cells
title_full	The demethylase inhibitor GSK-J4 limits inflammatory colitis by promoting de novo synthesis of retinoic acid in dendritic cells
title_fullStr	The demethylase inhibitor GSK-J4 limits inflammatory colitis by promoting de novo synthesis of retinoic acid in dendritic cells
title_full_unstemmed	The demethylase inhibitor GSK-J4 limits inflammatory colitis by promoting de novo synthesis of retinoic acid in dendritic cells
title_sort	demethylase inhibitor gsk-j4 limits inflammatory colitis by promoting de novo synthesis of retinoic acid in dendritic cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/64dc632d8ccf474eadb8e5911839b251
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The demethylase inhibitor GSK-J4 limits inflammatory colitis by promoting de novo synthesis of retinoic acid in dendritic cells

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