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

Cristian Doñas, Jocelyn Neira, Francisco Osorio-Barrios, Macarena Carrasco, Dominique Fernández, Carolina Prado, Alejandra Loyola, Rodrigo Pacheco, Mario Rosemblatt

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number1342
JournalScientific Reports
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 2021
Externally publishedYes

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'The demethylase inhibitor GSK-J4 limits inflammatory colitis by promoting de novo synthesis of retinoic acid in dendritic cells'. Together they form a unique fingerprint.

Cite this