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Hypersensitive interferon responses in lupus keratinocytes reveal key mechanistic determinants in cutaneous lupus

ABSTRACT: SLE patients exhibit increased interferon signatures in their skin secondary to increased production and a robust, skewed IFN response that is regulated by PITX1. Targeting of these exaggerated pathways may prove to be beneficial to prevent and treat hyperinflammatory responses in SLE skin.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124939 | GEO | 2019/01/15

REPOSITORIES: GEO

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Hypersensitive IFN Responses in Lupus Keratinocytes Reveal Key Mechanistic Determinants in Cutaneous Lupus.

Project description: Not available

| S-EPMC6424612 | biostudies-literature

Hypersensitive interferon responses in lupus keratinocytes reveal key mechanistic determinants in cutaneous lupus

Project description:Hypersensitive interferon responses in lupus keratinocytes reveal key mechanistic determinants in cutaneous lupus

| PRJNA514365 | ENA

Hippo pathway component WWC1 is a key regulator of apoptosis and photosensitivity in lupus keratinocytes

Project description:Skin inflammation and photosensitivity are common manifestations of cutaneous and systemic lupus erythematosus (SLE), yet the underlying mechanisms are poorly understood. Non-lesional SLE skin exhibits increased UVB-driven cell death that persists in culture, supporting a potential role for epigenetic modifications to sustain this phenotype. We thus examined differential DNA methylation of non-lesional SLE vs. healthy control keratinocytes (KC) and identified Hippo signaling as the top significantly differentially methylated pathway, likely driven by hypomethylation of WWC1, a scaffold protein and Hippo pathway regulator. Analysis of non-lesional SLE skin biopsies and SLE keratinocytes in culture confirmed WWC1 overexpression that led to enhanced phosphorylation of YAP resulting in a pro-apoptotic transcriptional profile reflective of decreased YAP/TEAD transcriptional coactivation. Functional studies of UV-mediated apoptosis confirmed a regulatory role for YAP/TEAD interactions, and blockade of overactive Hippo signaling via a LATS1/2 inhibitor abrogated enhanced apoptosis in SLE KCs. Thus, our work identifies a novel mechanistic paradigm in SLE KCs in which aberrant UVB-apoptosis is driven by Hippo signaling via promotion of YAP phosphorylation and restriction of YAP coactivation of TEAD transcriptional activity. Hippo modulation may be a novel target for photosensitivity in SLE and CLE.

2023-07-06 | GSE198972 | GEO

Human Neutrophils Phosphoproteome in Systemic Lupus Erythematosus

Project description:This study used proteomic, biomechanical, and functional analyses to further define neutrophil heterogeneity in the context of SLE. Mass spectrometry proteomic and phosphoproteomic analyses were performed in healthy control normal density neutrophils (NDNs), SLE NDNs and in autologous SLE LDGs. Proteomic and phosphoproteomic differences were detected when comparing control to SLE neutrophils and when comparing SLE NDNs to SLE LDGs.

2021-11-04 | PXD021096 | Pride

Gene expression of skin biopsie samples from juvenile myositis (JM) and childhood-onset lupus (cSLE).

Project description:Skin inflammaton heralds systemic disease in juvenile myositis (JM), yet we lack an understanding of pathogenic mechanisms driving skin inflammation in JM. The goal of this study is to define cutaneous gene expression signatures in JM and identify key genes and pathways that differentiate skin disease in JM from childhood-onset SLE (cSLE).

2020-12-31 | GSE148810 | GEO

Lupus dermal fibroblasts hyper-respond to inflammatory cytokines and exhibit a pro-fibrotic phenotype to TGF-β in patients with scarring skin disease

Project description:we examined responses to cytokines in dermal fibroblasts from the skin of SLE patients with CLE and healthy control volunteers to identify the inflammatory phenotype and gene expression profile associated with SLE and scarring CLE lesions.

2024-04-03 | GSE237690 | GEO

SLE lupus RNA-seq

Project description:RNA-seq of systemic lupus erythematosus (SLE) whole blood and healthy controls to determine the gene expression changes in these patients. RNA-seq of PAXgene blood from SLE and healthy donors.

2015-09-16 | E-GEOD-72509 | biostudies-arrayexpress

Genome-wide peripheral blood transcriptome analysis of Arab female Lupus and Lupus nephritis

Project description:Genome-wide alternative splice analysis of RNA from lupus and its severe form lupus nephritis We aimed to explore the genome-wide peripheral blood transcriptome of lupus (SLE) and its severe form lupus nephritis (LN) cases compared to healthy subjects (HC) using high density Affymetrix Human Exon1.0.ST arrays. Analysis revealed 15 splice variants that are differentially expressed between SLE/HC and 99 variants between LN/HC (p≤0.05,SI>or≤0.5,Benjamin Hochberg-False discovery rate correction). Comparison between LN/SLE revealed 7 variants that are differentially expressed with p≤0.05,SI>0.5,Benjamin Hochberg-FDR correction. Pathway analysis of differentially spliced genes revealed 11 significant pathways in SLE and 12 in LN (p<0.05). Analysis of peripheral blood transcriptome revealed signature causative genes that are alternatively spliced, signifying their clinical relevance in the pathophysiology of disease. The extent of differential splicing was found to be higher in LN than in SLE, signifying the need for further in-depth research in the same domain. Present study is the first to reveal the significance of alternative variants in susceptibility to SLE and LN.

2016-01-06 | GSE62764 | GEO

Genome-wide peripheral blood transcriptome analysis of Arab female Lupus and Lupus nephritis

Project description:Genome-wide alternative splice analysis of RNA from lupus and its severe form lupus nephritis We aimed to explore the genome-wide peripheral blood transcriptome of lupus (SLE) and its severe form lupus nephritis (LN) cases compared to healthy subjects (HC) using high density Affymetrix Human Exon1.0.ST arrays. Analysis revealed 15 splice variants that are differentially expressed between SLE/HC and 99 variants between LN/HC (pâ¤0.05,SI>orâ¤0.5,Benjamin Hochberg-False discovery rate correction). Comparison between LN/SLE revealed 7 variants that are differentially expressed with pâ¤0.05,SI>0.5,Benjamin Hochberg-FDR correction. Pathway analysis of differentially spliced genes revealed 11 significant pathways in SLE and 12 in LN (p<0.05). Analysis of peripheral blood transcriptome revealed signature causative genes that are alternatively spliced, signifying their clinical relevance in the pathophysiology of disease. The extent of differential splicing was found to be higher in LN than in SLE, signifying the need for further in-depth research in the same domain. Present study is the first to reveal the significance of alternative variants in susceptibility to SLE and LN. We analyzed blood from 11 female subjects (5 lupus, 3 lupus nephritis and 3 healthy control) using the Affymetrix Human Exon 1.0 ST platform. Array data was processed by Alt Analyze and Genespring software. No techinical replicates were performed. One of the outiler sample (HC2) was excluded from further analysis.

2016-01-06 | E-GEOD-62764 | biostudies-arrayexpress

Global Phosphoproteomics Reveals Molecular Networks in Systemic Lupus Erythematosus

Project description:Systemic lupus erythematosus (SLE) is a systemic and heterogeneous autoimmune disease for which its treatment and phosphorylation-dependent regulatory mechanism remain elusive. Here, we aim to explore the molecular mechanism of phosphorylation regulation for SLE. We employed high-throughput Phosphoproteomics of peripheral blood mononuclear cells (PBMCs) from 126 patients with SLE remission stage (SLE_S), 70 patients with SLE active stage (SLE_A), 160 patients with RA, and 135 healthy controls (HC). An independent cohort that included 60 SLE_S, 35 SLE_A, 50 RA and 40 HC was used to validate the phosphosites via parallel reaction monitoring (PRM). We revealed upregulated pathways involved in cell adhesion and migration in patients with SLE (SLE_S and SLE_A) compared with HCs and RA. Expression pattern clustering analysis revealed several specifically upregulated phosphosites, and the leukocyte transendothelial migration was specifically enriched in SLE_A. We predicted several key kinases including MAP3Ks, MAP2Ks, IKKB and TBK1, and found that upregulated kinase activity is associated with increased phosphorylation of VCL, TLN1 and VAPB by kinases-substrate network analysis. These phosphorylated proteins also regulate the pathways related to cell adhesion and migration, and which have not been implicated in previous studies of SLE. Moreover, we validated these phosphosites with the same trend as 4D-LFQ data, including LCP1 S5, TLN1 S1201, TLN1 S1225, VCL S275 and VCL S579. In summary, the present study elucidates the changes of phosphosites, kinases and pathways in SLE, and may provide potentially novel targets for further mechanism exploration.

2023-03-11 | PXD025076 | Pride

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