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RNA binding protein DDX5 restricts RORγt+ Treg suppressor function to promote intestine inflammation.
Ma, Shengyun; Yang, Qiyuan; Chen, Nicholas; Zheng, Anna; Abbasi, Nazia; Wang, Gaowei; Patel, Parth R; Cho, Benjamin S; Yee, Brian A; Zhang, Lunfeng; Chu, Hiutung; Evans, Sylvia M; Yeo, Gene W; Zheng, Ye; Huang, Wendy Jia Men.
Affiliation
  • Ma S; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • Yang Q; NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA.
  • Chen N; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • Zheng A; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • Abbasi N; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • Wang G; Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  • Patel PR; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • Cho BS; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • Yee BA; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • Zhang L; Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA.
  • Chu H; Department of Pathology, University of California San Diego, La Jolla, CA, USA.
  • Evans SM; Chiba University-UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines (cMAV), University of California San Diego, La Jolla, CA, USA.
  • Yeo GW; Department of Pediatrics, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA.
  • Zheng Y; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
  • Huang WJM; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
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.
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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
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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