Effect of depletion of AIM2 on gene expression in psoriatic NETs-treated primary human keratinocytes
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PROVIDER: PRJNA894149 | ENA |
REPOSITORIES: ENA
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Project description:To investigate the function of the NET-AIM2 axis on keratinocyte activation during psoriasis, we established psoriatic NETs-treated primary human keratinocytes in which AIM2 has been knocked down by siRNA
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Project description:Dissecting the miRNome of psoriatic keratinocytes
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Project description:The psoKC (psoriatic keratinocyte) model is represnting the behavour of keratinocytes in the later or chronic stage of psoriasis in response to the main cytokines that constitute the characteristic cytokine milieu, namely IFNg and TNFa (mainly derived by Th1 cells), and IL-17 and IL-22 (mainly derived by Th17 cells).
Additionally, the model explores the role of exogenous PGE2 through the activation of EP4 receptor signaling. The response to the aforementioned stimuli was not only limited to the cell fate decisions of keratinocytes (proliferation, apoptosis or differentiation) but also include their effect on the psoriatic environment with respect to the secretion of ligands and intercellular-acting stimuli.
2022-12-14 | MODEL2109300001 | BioModels
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: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:Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, and its incidence is increasing globally. Chronic inflammation has been recognized as a risk factor for cSCC and inflammation is a typical feature of the progression of actinic keratosis lesions to invasive and metastatic cSCC. Inflammasomes are important components of the innate immune response involved in onset of inflammation. Inflammasome component AIM2 serves as a sensor for cytoplasmic double-strand DNA, and this way plays a key role in response to bacterial and viral colonization. Activation of inflammasome by cytoplasmic DNA in epidermal keratinocytes can promote the initiation of inflammation in autoimmune and autoinflammatory skin diseases. Whole transcriptome analysis of cSCC cells (n=8) and normal human epidermal keratinocytes (NHEKs, n=4) and oligonucleotide array-based expression analysis of cSCC cells (n=8) and normal human epidermal keratinocytes (NHEKs, n=5) revealed overexpression of AIM2 in cSCC cells (GSE66412 and GSE66368, respectively). We wanted to futher study the RNA expression profile of AIM2 knockdown cSCC cells.
2017-08-18 | GSE94270 | GEO
Project description:Absent in Melanoma 2 (AIM2) is a member of the HIN-200 family of hematopoietic, IFN-inducible nuclear proteins associated with infection defense and tumor pathology. Recently, AIM2 was found to act as a DNA sensor in innate immunity. In addition, a high frequency of AIM2-alterations was observed in microsatellite unstable tumors. To elucidate AIM2 function in colorectal tumors, we here addressed AIM2-responsive genes by microarray. Among genes up-regulated by AIM2, there were a number of interferon-stimulated genes (ISGs: IFIT1, IFIT2, IFIT3, IFI6, IRF7, ISG15, HLA-DRA, HLA-DRB, TLR3 and CIITA) as well as genes involved in intercellular adhesion and matrix remodeling. Expression of ISGs correlated with expression of AIM2 in ten different IFN-γ treated colorectal cancer cell lines. Moreover, knock-down of AIM2 resulted in reduced expression of HLA-DRA, HLA-DRB, and CIITA in IFN-γ treated cells. IFN-γ independent induction of HLA-DR genes and their encoded proteins was also demonstrated upon transient induction of AIM2. STAT-signaling was not involved in IFN-γ independent induction of ISGs, arguing against participation of cytokines released in an autocrine manner. Our data indicate that AIM2 mediates IFN-γ dependent and independent induction of several Interferon stimulated genes (ISGs) including genes encoding the MHC II antigens HLA-DRα and β. we used microarray techniques to define genes responsive to AIM2 expression in colorectal tumor cells. HCT116 is a colorectal tumour cell line with no evidence for AIM2 expression which served as background for gene transfection. B8 and D1 were transfected subclones with persisting expression of AIM2. Gene expression of B8 and D1 was compared with that of mock transfected control cells.
2012-12-13 | E-GEOD-24155 | biostudies-arrayexpress
Project description:Absent in Melanoma 2 (AIM2) is a member of the HIN-200 family of hematopoietic, IFN-inducible nuclear proteins associated with infection defense and tumor pathology. Recently, AIM2 was found to act as a DNA sensor in innate immunity. In addition, a high frequency of AIM2-alterations was observed in microsatellite unstable tumors. To elucidate AIM2 function in colorectal tumors, we here addressed AIM2-responsive genes by microarray. Among genes up-regulated by AIM2, there were a number of interferon-stimulated genes (ISGs: IFIT1, IFIT2, IFIT3, IFI6, IRF7, ISG15, HLA-DRA, HLA-DRB, TLR3 and CIITA) as well as genes involved in intercellular adhesion and matrix remodeling. Expression of ISGs correlated with expression of AIM2 in ten different IFN-γ treated colorectal cancer cell lines. Moreover, knock-down of AIM2 resulted in reduced expression of HLA-DRA, HLA-DRB, and CIITA in IFN-γ treated cells. IFN-γ independent induction of HLA-DR genes and their encoded proteins was also demonstrated upon transient induction of AIM2. STAT-signaling was not involved in IFN-γ independent induction of ISGs, arguing against participation of cytokines released in an autocrine manner. Our data indicate that AIM2 mediates IFN-γ dependent and independent induction of several Interferon stimulated genes (ISGs) including genes encoding the MHC II antigens HLA-DRα and β. we used microarray techniques to define genes responsive to AIM2 expression in colorectal tumor cells.
2012-12-13 | GSE24155 | GEO
Project description:CaMK4 has an important function in autoimmune diseases, and the contribution of CaMK4 in psoriasis remains obscure. Here, we show that CaMK4 expression is significantly increased in psoriatic lesional skin from psoriasis patients compared to healthy human skin as well as inflamed skin from an imiquimod (IMQ)-induced mouse model of psoriasis compared to healthy mouse skin. Camk4-deficient (Camk4−/−) mice treated with IMQ exhibit reduced severity of psoriasis compared to wild-type (WT) mice. There are more macrophages and fewer IL-17A+γδ TCR+ cells in the skin of IMQ-treated Camk4−/− mice compared to IMQ-treated WT mice. CaMK4 inhibits IL-10 production by macrophages, thus allowing excessive psoriatic inflammation. Deletion of Camk4 in macrophages alleviates IMQ-induced psoriatic inflammation in mice. In keratinocytes, CaMK4 inhibits apoptosis as well as promotes cell proliferation and the expression of pro-inflammatory genes such as S100A8 and CAMP. Taken together, these data indicate that CaMK4 regulates IMQ-induced psoriasis by sustaining inflammation and provides a potential target for psoriasis treatment.
2022-05-28 | GSE204832 | GEO