RNA binding protein DDX5 restricts RORγt ⁺ T _reg suppressor function to promote intestine inflammation

Abstract

Retinoid-related orphan receptor (RAR) gamma (RORγt)–expressing regulatory T cells (RORγt + T regs ) 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 + T regs . 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 + T regs . T cell–specific Ddx5 knockout (DDX5 ΔT ) mice have augmented RORγt + T reg suppressor activities and are better protected from intestinal inflammation. Genetic ablation or pharmacologic inhibition of HIF1α restores enteropathy susceptibility in DDX5 ΔT mice. The DDX5–HIF1α–IL-10 pathway is conserved in mice and humans. These findings reveal potential therapeutic targets for intestinal inflammatory diseases.

DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells

“…For instance, loss-of-function variants of MDA5, an important member of the RNA helicase family, have been implicated in very early onset IBD 40 . DDX5 has been shown to regulate the function of epithelial tuft cells and intestinal regulatory T cells, which control the microbial repertoire and inhibits intestinal inflammation 41 , 42 . However, the roles of most RNA helicases in regulating intestinal function remain unclear.…”

DDX5 enhances HIF‐1 activity by promoting the interaction of HIF‐1α with HIF‐1β and recruiting the resulting heterodimer to its target gene loci

“…Ma et al. reported that DDX5 suppresses HIF‐1‐dependent expression of the anti‐inflammation cytokine interleukin‐10 (IL‐10) in certain regulatory T cells under hypoxic conditions (Ma et al., 2023). On the other hand, in the present study, we found that aberrant expression of DDX5 activates HIF‐1 signaling in cancer cells.…”

The dynamic shifts of IL-10-producing Th17 and IL-17-producing Treg in health and disease: a crosstalk between ancient "Yin-Yang" theory and modern immunology

“…Given the dual regulatory potential of HIF-1α on T cells, its impact on IL-17-producing Treg differentiation and function has been studied. It has been confirmed that HIF-1α is one of the factors promoting IL-10 production in IL-17-producing Tregs [ 102 ]. High levels of HIF-1α are expressed in IL-17-producing Tregs within the lamina propria of the intestinal mucosa.…”

“…Consequently, Hif1a transcription is repressed, inhibiting HIF-1α-induced IL-10 production in IL-17-producing Tregs (Fig. 1 ) [ 102 ].…”