PMID- 33446666
OWN - NLM
STAT- MEDLINE
DCOM- 20210810
LR  - 20210810
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 11
IP  - 1
DP  - 2021 Jan 14
TI  - The demethylase inhibitor GSK-J4 limits inflammatory colitis by promoting de novo 
      synthesis of retinoic acid in dendritic cells.
PG  - 1342
LID - 10.1038/s41598-020-79122-3 [doi]
LID - 1342
AB  - 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.
FAU - Donas, Cristian
AU  - Donas C
AD  - Fundacion Ciencia & Vida, Av. Zanartu 1482, 7780272, Nunoa, Santiago, Chile.
FAU - Neira, Jocelyn
AU  - Neira J
AD  - Fundacion Ciencia & Vida, Av. Zanartu 1482, 7780272, Nunoa, Santiago, Chile.
AD  - Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life 
      Sciences, Universidad Andres Bello, Av. Republica 330, Santiago, Chile.
FAU - Osorio-Barrios, Francisco
AU  - Osorio-Barrios F
AD  - Fundacion Ciencia & Vida, Av. Zanartu 1482, 7780272, Nunoa, Santiago, Chile.
FAU - Carrasco, Macarena
AU  - Carrasco M
AD  - Fundacion Ciencia & Vida, Av. Zanartu 1482, 7780272, Nunoa, Santiago, Chile.
FAU - Fernandez, Dominique
AU  - Fernandez D
AD  - Fundacion Ciencia & Vida, Av. Zanartu 1482, 7780272, Nunoa, Santiago, Chile.
FAU - Prado, Carolina
AU  - Prado C
AD  - Fundacion Ciencia & Vida, Av. Zanartu 1482, 7780272, Nunoa, Santiago, Chile.
FAU - Loyola, Alejandra
AU  - Loyola A
AD  - Fundacion Ciencia & Vida, Av. Zanartu 1482, 7780272, Nunoa, Santiago, Chile.
AD  - Universidad San Sebastian, 7510156, Providencia, Santiago, Chile.
FAU - Pacheco, Rodrigo
AU  - Pacheco R
AD  - Fundacion Ciencia & Vida, Av. Zanartu 1482, 7780272, Nunoa, Santiago, Chile. 
      rpacheco@cienciavida.org.
AD  - Universidad San Sebastian, 7510156, Providencia, Santiago, Chile. 
      rpacheco@cienciavida.org.
FAU - Rosemblatt, Mario
AU  - Rosemblatt M
AD  - Fundacion Ciencia & Vida, Av. Zanartu 1482, 7780272, Nunoa, Santiago, Chile. 
      mrosemblatt@cienciavida.org.
AD  - Universidad San Sebastian, 7510156, Providencia, Santiago, Chile. 
      mrosemblatt@cienciavida.org.
AD  - Departamento de Biologia, Facultad de Ciencias, Universidad de Chile, 7800003, 
      Santiago, Chile. mrosemblatt@cienciavida.org.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210114
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Benzazepines)
RN  - 0 (GSK-J4)
RN  - 0 (Pyrimidines)
RN  - 5688UTC01R (Tretinoin)
RN  - EC 1.2.1 (Aldehyde Dehydrogenase 1 Family)
RN  - EC 1.2.1.36 (ALDH1A1 protein, mouse)
RN  - EC 1.2.1.36 (Retinal Dehydrogenase)
RN  - EC 1.2.1.36 (retinaldehyde dehydrogenase 3, mouse)
SB  - IM
MH  - Aldehyde Dehydrogenase 1 Family/genetics/immunology
MH  - Animals
MH  - Benzazepines/*pharmacology
MH  - Colitis/drug therapy/genetics/*immunology/pathology
MH  - Dendritic Cells/*immunology/pathology
MH  - Inflammatory Bowel Diseases/drug therapy/genetics/*immunology/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Pyrimidines/*pharmacology
MH  - Retinal Dehydrogenase/genetics/immunology
MH  - T-Lymphocytes, Regulatory/immunology/pathology
MH  - Th1 Cells/immunology/pathology
MH  - Th17 Cells/immunology/pathology
MH  - Tretinoin/*immunology
PMC - PMC7809056
COIS- J.N., F.O.-B., D.F., C.P. and R.P. declare that they do not have any financial or 
      non-financial competing interests. C.D., M.C., A.L. and M.R. are authors of a 
      pending patent application describing the therapeutic use of using GSK-J4 as 
      treatment for inflammatory bowel diseases.
EDAT- 2021/01/16 06:00
MHDA- 2021/08/11 06:00
PMCR- 2021/01/14
CRDT- 2021/01/15 05:53
PHST- 2020/03/31 00:00 [received]
PHST- 2020/11/26 00:00 [accepted]
PHST- 2021/01/15 05:53 [entrez]
PHST- 2021/01/16 06:00 [pubmed]
PHST- 2021/08/11 06:00 [medline]
PHST- 2021/01/14 00:00 [pmc-release]
AID - 10.1038/s41598-020-79122-3 [pii]
AID - 79122 [pii]
AID - 10.1038/s41598-020-79122-3 [doi]
PST - epublish
SO  - Sci Rep. 2021 Jan 14;11(1):1342. doi: 10.1038/s41598-020-79122-3.