MiR-378a regulates keratinocyte responsiveness to IL-17A in psoriasis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE164400 | GEO | 2021/03/08
REPOSITORIES: GEO
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Project description:We report the high-throughput profiling of human primary keratinocytes transfected with either miR-378 mimic or miR-378 inhibitor at 24 or 48 hours. Our study focused on the dysregulation of microRNAs that might partially be a fundamental mechanism leading to psoriasis development. We knock-in and knock-out a specific miR-378 and see the cellular responses. As expected, overexpression of miR-378a inhibited the proliferation, enhanced the apoptosis and disturbed the cell cycle. Regarding to the confirm experiment, our results suggested that the expression of miR-378a associated with the psoriasis pathogenesis enhancing the severity of psoriatic lesion, and might useful for further development of therapeutic strategy for psoriasis.
2020-11-06 | GSE160906 | GEO
Project description:Purpose: The purpose of this study was to identify the miRNome of keratinocytes in psoriasis Method: We performed next-generation sequencing for small RNAs from the RNA samples obtained from keratinocytes from psoriasis lesional, non-lesional and healthy skin. Next, we removed adapters and the low quality tags from the sequencing data and clean reads were mapped and aligned to known miRNAs sequences (miRBase 21). Novel miRNA transcripts were predicted based on the length (22-25 nucleotide) and secondary structure (precursor analysis) using MIREAP and mapped to the human genome. Data were normalized (transcripts per million, TPM) and analysed using Bioconductor-EdgeR. Group comparisons (lesional vs. healthy, lesional vs. non lesional and non-lesional vs. healthy) were performed. MiRNAs with <10% FDR, fold change >1.4 (1 TPM at least in one of the groups and expressed in half of the samples in any group) were considered statistically significant. Results: Robust expression of 411 known and 30 novel miRNAs (TPM > 1 in >50% of the samples in at least one of the groups) was detected in our samples. Using EdgeR we identified 104 miRNAs with significantly altered level (fold change > 1.4, FDR < 0.1) between healthy and psoriatic keratinocytes (P vs H). While, pair-wise comparison of miRNA expression in keratinocytes from non-lesional and lesional psoriasis skin (P vs. N) identified 87 deregulated miRNAs. Comparison of the miRNome of keratinocytes from non-lesional skin of psoriasis patients to healthy keratinocytes (N vs. H) identified 7 differentially expressed miRNAs. Conclusion: Here, for the first time we show the keratinocyte miRNome in psoriasis which may serve as the basis for future functional studies of miRNAs deregulated in keratinocytes in psoriasis.
2019-07-23 | GSE129373 | GEO
Project description:To gain further knowledge on the role of microRNAs (miRNAs) in the pathogenesis of Burkitt lymphoma (BL), we performed small RNA sequencing in BL cell lines and normal germinal center B (GC-B) cells. This revealed 26 miRNAs with significantly different expression levels. Altered levels were validated by qRT-PCR for six of eight selected miRNAs. For five miRNAs, the differential expression pattern was confirmed in BL primary tissues compared to GC-B cells. Inhibition of miR-378a-3p reduced the growth of multiple BL cell lines. RNA immunoprecipitation of Argonaute 2 followed by microarray analysis (Ago2-RIP-Chip) upon inhibition and ectopic overexpression of miR-378a-3p revealed 63 and 20 putative miR-378a-3p targets, respectively. These included 28 genes with a putative miR-378a-3p binding site. Effective targeting by miR-378a-3p was confirmed by luciferase reporter assays for four out of eight selected genes: MNT, FOXP1, IRAK4, and lncRNA JPX, all of which have been implicated in proliferation and cancer. In summary, our study identified several differentially expressed miRNAs in BL. We identified miR-378a-3p as a miRNA with an oncogenic role in BL and revealed 4 novel miR-378a-3p target genes, i.e. MNT, FOXP1, IRAK4, and JPX.
2020-06-30 | GSE141691 | GEO
Project description:miR-378a regulates keratinocyte responsiveness to IL-17A in psoriasis
| PRJNA690544 | ENA
Project description:Psoriasis is a systemic disease with cutaneous manifestations. MicroRNAs (miRNAs) are non-coding RNA molecules that are differentially expressed in psoriatic skin, however; only few miRNAs have been localized to specific cells or regions of psoriatic lesions. We used laser capture microdissection (LCM) and next-generation sequencing to study the specific miRNA expression profiles in the epidermis (Epi) and dermal inflammatory aggregates (RD/ICs) of psoriatic skin. We identified 24 deregulated miRNAs in the Epi and 37 deregulated miRNAs in the RD/ICs of lesional psoriatic skin compared with non-lesional psoriatic skin (FCH>2, FDR<0.05). Interestingly, 9 of the 37 miRNAs, including miR-193b and miR-223 that have recently been described as deregulated in circulating peripheral blood mononuclear cells (PBMCs) from patients with psoriasis. Using flow cytometry and qRT-PCR, miR-193b and miR-223 were found to be expressed in Th17 cells. In conclusion, we demonstrate that LCM combined with small RNA sequencing provides a robust strategy to explore the global miRNA expression in the epidermal and dermal compartments of psoriatic skin. Furthermore, our results indicate that the altered local miRNA changes seen in the RD/ICs is reflected in the circulating immune cells, altogether emphasizing that miRNAs may contribute to a systemic component in the pathogenesis of psoriasis. Examination of the global miRNA expression in epidermis (Epi) and dermis (RD/ICs) of paired (non-lesional vs. lesional) psoriatic skin using a combination of laser-capture microdissection and barcoded small RNA sequencing
2015-04-01 | E-GEOD-57012 | biostudies-arrayexpress
Project description:Wild-type (WT) miR-378a-3p or edited miR-378a-3p were expressed in SB2 KD-ADAR1 cells to identify the genes regulated by edited miR-378a-3p vs WT miR-378a-3p. PARVA was one of the genes identified to be regulated by edited miR-378a-3p. We demonstrate that this regulation of PARVA is lost in highly metastatic melanoma cells. Microarray analysis was used to evaluate the robustness and reproducibility of the method used to generate the ex vivo tumor tissue model and confirm its ability to recapitulate the essential features of the original tumor.
2018-02-22 | GSE107088 | GEO
Project description:The efficacy of monoclonal antibodies against either interleukin (IL)-17 or the IL-17 receptor in psoriasis therapy provides strong evidence that IL-17 is the major inflammatory mediation in this disease. However, how IL-17 induces epidermal hyperplasia in psoriasis remains largely unknown. Here, we show that IL-17 actives NF-kB in keratinocytes and initiates the NF-kB-dependent transcription of microRNA-31 (miR-31), one of the most abundant microRNAs in the epidermis of lesional skin of psoriasis and two related mouse models. Similar to IL-17 deficiency (IL-17-/-), knocking out miR-31 (miR-31-/-) or targeting it by antagomir-31 prevents keratinocytes Ki67 expression and inhibits acanthosis and dermal inflammation in psoriasis mouse model. Moreover, PPP6c, a negative regulator restricting G0/G1 to G2/M phase progression in the cell cycle, is diminished in human psoriatic epidermis and is directly targeted by miR-31. Inhibition of ppp6c is functionally important for the biological effects of miR-31 in the development of epidermal hyperplasia. Thus, our data define IL-17-inducede miR-31 and its target ppp6c as critical factors for hyperproliferative epidermis in psoriasis. Epidermis samples from affected ears derived from 3 CD18hypo PL/J mice (DIS) or normal ears derived from 3 CD18hypo C57BL/6J mice(2128) were used for RNA extraction and hybridization on Affymetrix microarrays. We sought to compare miRNA expression of normal skin from control and lesional skin.
2013-12-31 | E-GEOD-50099 | biostudies-arrayexpress
Project description:Next to genetic alterations, it is being recognized that the cellular environment also acts as a major determinant in onset and progression of disease. In cases where different cell types contribute to the final disease outcome, this imposes environmental challenges as different cell types likely differ in their extracellular dependencies. A number of skin diseases, including psoriasis is characterized by a combination of keratinocyte hyperproliferation and immune cell activation. Activation of immune cells involves increased glucose consumption thereby intrinsicly limiting glucose availability for other cell types. Thus, these type of skin diseases require metabolic adaptations that enable coexistence between hyperproliferative keratinocytes and activated immune cells in a nutrient-limited environment. Hsa-microRNA-31-5p (miR-31) is highly expressed in keratinocytes within the psoriatic skin. Here we show that miR-31 expression in keratinocytes is induced by limited glucose availability and enables increased survival of keratinocytes under limiting glucose conditions, by increasing glutamine metabolism. In addition, miR-31 induced glutamine metabolism results in secretion of specific metabolites (aspartate and glutamate) but also secretion of immuno-modulatory factors. We show that this miR-31-induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibition of glutaminase (GLS) using CB-839 impedes miR31-induced metabolic rewiring and secretion of immuno-modulatory factors. Concordantly, pharmacological targeting of GLS alleviated psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis.
2023-02-06 | PXD029030 | Pride
Project description:MiR-31 is one of the most highly overexpressed miRNAs in psoriasis skin; however, its biological role in the disease has not been studied. Here we show that miR-31 is markedly overexpressed in psoriasis keratinocytes. To study the biological role of miR-31 in keratinocytes, we transfected miR-31 hairpin inhibitor (anti-miR-31) into primary human keratinocytes to inhibit endogenous miR-31. We performed a global transcriptome analysis of keratinocytes upon suppression of endogenous miR-31 using Affymetrix arrays.
2012-10-30 | GSE41905 | GEO
Project description:Durable psoriasis improvement has been reported in a subset of psoriasis patients after treatment withdrawal of biologics blocking IL-23/Type 17 T-cell (T17) autoimmune axis. However, it is not well understood if systemic blockade of the IL-23/T17 axis promotes immune tolerance in psoriasis skin. The purpose of the study was to find translational evidence that systemic IL-17A blockade promotes regulatory transcriptome modification in human psoriasis skin immune cell subsets. We analyzed human psoriasis lesional skin 6 mm punch biopsy tissues before and after systemic IL-17A blockade using the muti-genomics approach integrating immune cell-enriched scRNA-seq (n = 18), microarray (n = 61), and immunohistochemistry (n = 61) with repository normal control skin immune cell-enriched scRNA-seq (n = 10) and microarray (n = 8) data. For the T17 axis transcriptome, systemic IL-17A blockade depleted 100% of IL17A + T-cells and 95% of IL17F + T-cells in psoriasis skin. The expression of IL23A in DC subsets was also downregulated by IL-17A blockade. The expression of IL-17-driven inflammatory mediators (IL36G, S100A8, DEFB4A, and DEFB4B) in suprabasal keratinocytes was correlated with psoriasis severity and was downregulated by IL-17A blockade. For the regulatory DC transcriptome, the proportion of regulatory semimature DCs expressing regulatory DC markers of BDCA-3 (THBD) and DCIR (CLEC4A) was increased in posttreatment psoriasis lesional skin compared to pretreatment psoriasis lesional skin. In addition, IL-17A blockade induced higher expression of CD1C and CD14, which are markers of CD1c+ CD14+ dendritic cell (DC) subset that suppresses antigen-specific T-cell responses, in posttreatment regulatory semimature DCs compared to pretreatment regulatory semimature DCs. In conclusion, systemic IL-17A inhibition not only blocks the entire IL-23/T17 cell axis but also promotes regulatory gene expression in regulatory DCs in human psoriasis skin.
2023-09-04 | GSE183047 | GEO