Keratinocyte DDX5 in response to IL-36γ
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE208666 | GEO | 2022/10/24
REPOSITORIES: GEO
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Project description:The DEAD-box (DDX) proteins function in diverse cellular processes including RNA alternative splicing, and are linked to immune-mediated diseases. However, little is known about the roles of DDXs in skin inflammatory diseases. Here, we show that DDX5, one of the founding members of the DDX RNA helicase family, controls skin inflammation and participates in the pathogenesis of psoriasis via regulating IL-36R pre-mRNA splicing. We found that both mRNA and protein of DDX5 are decreased in lesional skin from patients with psoriasis and psoriasis-like mice, and that mice with keratinocyte-specific ablation of DDX5 spontaneously develop psoriasis-like phenotypes. Mechanistically, DDX5 complexes with serine/arginine-rich splicing factor 1(SRSF1) to typically regulate IL-36R pre-mRNA splicing in keratinocytes, which generates mRNAs encoding full-length IL-36R and a previously unknown soluble form of IL-36R (sIL-36R). sIL-36R controls IL-36/IL-36R signaling by competing with IL-36R for IL-36γ ligation. The reduction or deficiency of DDX5 leads to IL-36R pre-mRNA splicing preferring to the generation of IL-36R but not sIL-36R, thereby selectively amplifying inflammatory responses of keratinocytes to IL-36γ and then aggravating cutaneous inflammation in psoriasis. Genetic restoration or intradermal administration of sIL-36R in psoriasis-like mice suppresses IL-36R signaling and alleviates the disease phenotype of psoriasis. Altogether, these data reveal a pathogenic role of DDX5 during psoriasis, and provide mechanistic insights into the regulation of IL-36R splicing and its impact on psoriasis development.
2020-09-09 | PXD021379 | iProX
Project description:Keratinocytes isolated from one healthy donor were stimulated in triplicate for 24h with IL-36α, IL-36β or IL-36γ
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Project description:DDX5, a DEAD box containing RNA binding protein, is involved in multiple aspects of RNA metabolism and is abundantly expressed in all subsets of the intestinal epithelial cells (IEC). Here, we characterized the DDX5-dependent transcriptome in the small intestine. In the DDX5△IEC tissue, we found that secretory IEC lineage progenitor containing spots (Atoh1hi and Sox4hi) had reduced expression of Pou2f3, a master regulator of a subset of IECs called tuft cells. As a result of the loss of Pou2f3 expression in the progenitors, DDX5△IEC tissue harbored lower number of tuft cell containing spots (Dclk1hi) compare to WT tissues.
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Project description:Ts keratinocyte has increased proliferation compare to WT keratinocyte upon TPA treatment. This result showed the different transcription regulation in Ts and WT keratinocyte upon TPA treatment. Total RNA extracted from WT or Ts keratinocytes, not treated or treated with TPA for 12 hours.
2013-06-01 | E-GEOD-40382 | biostudies-arrayexpress
Project description:RAR-related orphan receptor gamma (ROR t)-expressing regulatory T (ROR t+ Treg) cells 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 1a (HIF1alpha) is the master transcription factor for *Il10* in ROR t+ Tregs. Interestingly, 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 HIF1 and its downstream target gene *Il10* in ROR t+ Tregs. T cell specific *Ddx5* knockout (DDX5 T) mice have augmented ROR t+ Treg suppressor activities and are better protected from intestinal inflammation. Genetic ablation or pharmacologic inhibition of HIF1a restores enteropathy susceptibility in DDX5 T mice. The DDX5-HIF1 -IL-10 pathway is conserved in mice and humans. These findings reveal potential therapeutic targets for intestinal inflammatory diseases.
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Project description:The aim of this study was to establish an intradermal ear injection model to evaluate the effects of IL-36γ and IL-17A in psoriasis.The cytokines IL-36γ and IL-17A were injected intradermally alone or in combination into the ear pinnae of C57BL/6 mice. Ear thickness measurement was performed daily. After 4 days mice were euthanized and a gene expression profiling was conducted.
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Project description:To investigate whether DDX5 is involved in the development of psoriasis,we performed gene expression profiling analysis using data obtained from RNA-seq of ear skins from Ddx5f/f and K14Ddx5f/f psoriatic mice
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Project description:Purpose: The goals of this study are to compare RNAs bound by DDX5 and RORgt in cultured T helper 17 cell in wildtype background. Methods: Th17 mRNA profiles of 48hrs in vitro cultured T helper 17 cells from wild-type mice were generated by deep sequencing, using Illumina HighSeq. The sequence reads that passed quality filters were analyzed at the transcript isoform level with two methods: BurrowsâWheeler Aligner (BWA) and TopHat followed by CuffDiff. qRTâPCR validation was performed using SYBR Green assays. Results: Among the 3444 RefSeq non-coding RNAs and 46449 NONCODE non-coding RNAs, 2533 were found to be expressed in Th17 cells (FPKM>1). 210 of them were enriched in DDX5 pull-down and 119 of them were enriched in RORgt pull-down. Conclusions: Our study suggest that a subset of 31 ncRNAs were co-enriched in DDX5 and RORgt pull-down. DDX5 or RORgt-associated-RNA profiles of 48hr in vitro cultured Th17 from wild type (WT) mice were generated by deep sequencing using Illumina HighSeq
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Project description:Hyaloid cartilage fibrosis is one of the important reasons for the poor prognosis of advanced osteoarthritis (OA), and is the main factor leading to joint stiffness and deformity. However, the mechanism of hyaline cartilage fibrosis remains largely unclear. Here we report that DDX5, one of the founding members of the DEAD-box RNA helicase family, was dramatically down-regulated in the degenerated articular cartilage of aged mice, and patients with OA, mouse destabilization of the medial meniscus (DMM) models，and cytokine (Interleukin (IL)-1β and tumor necrosis factor (TNF)-α) stimulation.In vitro and in vivo experimental findings that inhibition of DDX5 expression increases the fibrocartilage phenotype by reduction collagen type I (COL I) protein expression and up-regulate collagen type II (COL II) protein expression. In addition, The reduction of DDX5 aggravate cartilage degradation by induce the production of cartilage degrading enzymes. In addition, DDX5 induced exon 25 skip of FN1-AS and exon 14 skip of PLOD2-AS produced a transcript (termed FN1-AS1-SE25 and PLOD2-AS-SE14). The reduction in DDX5 results in an increase in the FN1-AS-WT and PLOD2-AS-WT variants.
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