Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA.
Sci Adv. 2023 Feb 3;9(5):eadd6165. doi: 10.1126/sciadv.add6165. Epub 2023 Feb 1.
Retinoid-related orphan receptor (RAR) gamma (RORγt)-expressing regulatory T cells (RORγt T) 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 in RORγt T. 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 in RORγt T. T cell-specific knockout (DDX5) mice have augmented RORγt T suppressor activities and are better protected from intestinal inflammation. Genetic ablation or pharmacologic inhibition of HIF1α restores enteropathy susceptibility in DDX5 mice. The DDX5-HIF1α-IL-10 pathway is conserved in mice and humans. These findings reveal potential therapeutic targets for intestinal inflammatory diseases.
维甲酸相关孤儿受体（RAR）γ（RORγt）表达的调节性 T 细胞（RORγt T）通过分泌抗炎细胞因子白细胞介素-10（IL-10），在防止 T 细胞过度激活和维持组织内稳态方面发挥关键作用。在这里，我们报告缺氧诱导因子 1α（HIF1α）是 RORγt T 中 的主要转录因子。这种关键的抗炎途径受 RNA 结合蛋白 DEAD 盒解旋酶 5（DDX5）的负调控。作为转录共抑制因子，DDX5 限制了 RORγt T 中 HIF1α及其下游靶基因 的表达。T 细胞特异性 DDX5 敲除（DDX5）小鼠增强了 RORγt T 的抑制活性，并更好地免受肠道炎症的影响。HIF1α 的基因缺失或药理学抑制恢复了 DDX5 小鼠的肠病易感性。DDX5-HIF1α-IL-10 通路在小鼠和人类中是保守的。这些发现为肠道炎症性疾病提供了潜在的治疗靶点。
