RNA binding protein DDX5 restricts RORγt+ Treg suppressor function to promote intestine inflammation.
Sci Adv
; 9(5): eadd6165, 2023 02 03.
Article
in En
| MEDLINE
| ID: mdl-36724232
ABSTRACT
Retinoid-related orphan receptor (RAR) gamma (RORγt)-expressing regulatory T cells (RORγt+ Tregs) play pivotal roles in preventing T cell hyperactivation and maintaining tissue homeostasis, in part by secreting the anti-inflammation cytokine interleukin-10 (IL-10). Here, we report that hypoxia-induced factor 1α (HIF1α) is the master transcription factor for Il10 in RORγt+ Tregs. This critical anti-inflammatory pathway is negatively regulated by an RNA binding protein DEAD box helicase 5 (DDX5). As a transcriptional corepressor, DDX5 restricts the expression of HIF1α and its downstream target gene Il10 in RORγt+ Tregs. T cell-specific Ddx5 knockout (DDX5ΔT) mice have augmented RORγt+ Treg suppressor activities and are better protected from intestinal inflammation. Genetic ablation or pharmacologic inhibition of HIF1α restores enteropathy susceptibility in DDX5ΔT mice. The DDX5-HIF1α-IL-10 pathway is conserved in mice and humans. These findings reveal potential therapeutic targets for intestinal inflammatory diseases.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Interleukin-10
/
Nuclear Receptor Subfamily 1, Group F, Member 3
Limits:
Animals
/
Humans
Language:
En
Journal:
Sci Adv
Year:
2023
Document type:
Article
Affiliation country:
United States