Itaconate ameliorates autoimmunity by modulating T cell imbalance via metabolic and epigenetic reprogramming.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 02 2023
27 02 2023
Historique:
received:
14
10
2021
accepted:
07
02
2023
entrez:
27
2
2023
pubmed:
28
2
2023
medline:
3
3
2023
Statut:
epublish
Résumé
Dysregulation of Th17 and Treg cells contributes to the pathophysiology of many autoimmune diseases. Herein, we show that itaconate, an immunomodulatory metabolite, inhibits Th17 cell differentiation and promotes Treg cell differentiation by orchestrating metabolic and epigenetic reprogramming. Mechanistically, itaconate suppresses glycolysis and oxidative phosphorylation in Th17- and Treg-polarizing T cells. Following treatment with itaconate, the S-adenosyl-L-methionine/S-adenosylhomocysteine ratio and 2-hydroxyglutarate levels are decreased by inhibiting the synthetic enzyme activities in Th17 and Treg cells, respectively. Consequently, these metabolic changes are associated with altered chromatin accessibility of essential transcription factors and key gene expression in Th17 and Treg cell differentiation, including decreased RORγt binding at the Il17a promoter. The adoptive transfer of itaconate-treated Th17-polarizing T cells ameliorates experimental autoimmune encephalomyelitis. These results indicate that itaconate is a crucial metabolic regulator for Th17/Treg cell balance and could be a potential therapeutic agent for autoimmune diseases.
Identifiants
pubmed: 36849508
doi: 10.1038/s41467-023-36594-x
pii: 10.1038/s41467-023-36594-x
pmc: PMC9970976
doi:
Substances chimiques
itaconic acid
Q4516562YH
Succinates
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
984Informations de copyright
© 2023. The Author(s).
Références
Nat Rev Immunol. 2015 Sep 15;15(9):545-58
pubmed: 26250739
Nat Immunol. 2020 Jun;21(6):605-614
pubmed: 32367037
J Cell Biol. 2018 Jul 2;217(7):2247-2259
pubmed: 29760106
Cell Metab. 2016 Jul 12;24(1):158-66
pubmed: 27374498
Nat Methods. 2017 Oct;14(10):959-962
pubmed: 28846090
Nat Metab. 2020 Jul;2(7):594-602
pubmed: 32694786
Trends Immunol. 2019 Aug;40(8):687-698
pubmed: 31178405
Mod Rheumatol. 2019 Jan;29(1):60-69
pubmed: 29947283
Annu Rev Immunol. 2010;28:445-89
pubmed: 20192806
Cell. 2007 Feb 23;128(4):693-705
pubmed: 17320507
Nat Commun. 2020 Oct 2;11(1):4938
pubmed: 33009401
Cell. 2012 Oct 12;151(2):289-303
pubmed: 23021777
Cell. 2011 Sep 2;146(5):772-84
pubmed: 21871655
J Biol Chem. 2011 May 6;286(18):16374-85
pubmed: 21454555
Nature. 2017 Aug 10;548(7666):228-233
pubmed: 28783731
Genome Biol. 2014;15(12):550
pubmed: 25516281
J Bacteriol. 1977 Jul;131(1):136-44
pubmed: 17593
Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):9288-9293
pubmed: 30150402
Physiol Rev. 2009 Jan;89(1):73-120
pubmed: 19126755
Nat Chem Biol. 2019 Oct;15(10):983-991
pubmed: 31332308
Immunity. 2020 Feb 18;52(2):342-356.e6
pubmed: 32023490
Nature. 2018 Apr 5;556(7699):113-117
pubmed: 29590092
Lancet. 2019 Jun 8;393(10188):2332-2343
pubmed: 31180030
Nat Commun. 2016 Sep 29;7:12993
pubmed: 27680869
Nat Rev Immunol. 2019 May;19(5):273-281
pubmed: 30705422
Arthritis Rheum. 2012 Aug;64(8):2499-503
pubmed: 22488116
Cell Rep. 2015 Aug 11;12(6):1042-55
pubmed: 26235623
Cell Metab. 2020 Feb 4;31(2):250-266.e9
pubmed: 32023446
Nat Rev Immunol. 2017 Nov;17(11):703-717
pubmed: 28757603
Nat Methods. 2013 Dec;10(12):1213-8
pubmed: 24097267
Nature. 2018 Apr;556(7702):501-504
pubmed: 29670287
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Cell. 2021 Aug 5;184(16):4168-4185.e21
pubmed: 34216539
Annu Rev Immunol. 2018 Apr 26;36:461-488
pubmed: 29677474
Nat Rev Rheumatol. 2020 Feb;16(2):100-112
pubmed: 31949287
Immunity. 2012 Jan 27;36(1):23-31
pubmed: 22244845
Cell Metab. 2014 Jul 1;20(1):61-72
pubmed: 24930970
Nat Cell Biol. 2022 Mar;24(3):353-363
pubmed: 35256775
Genes Cells. 2013 Apr;18(4):247-65
pubmed: 23383714
JCI Insight. 2019 Jun 20;4(12):
pubmed: 31217348
J Exp Med. 2021 Jun 7;218(6):
pubmed: 34037676
Cancer Cell. 2012 Jul 10;22(1):66-79
pubmed: 22789539
Immunol Rev. 2014 Sep;261(1):62-83
pubmed: 25123277
Front Chem. 2021 May 12;9:669308
pubmed: 34055739
Nat Commun. 2019 Apr 3;10(1):1523
pubmed: 30944313
Nature. 2008 May 8;453(7192):236-40
pubmed: 18368049
Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):2478-2483
pubmed: 29463741