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RNA-seq of primary human keratinocytes and primary mouse trigeminal ganglion neurons: Effects of IL-27 and BST2 on gene expression

ABSTRACT: In the present study, RNA-seq were performed To explore biological significance of IL-27 and BST2 in the neuro-cutaneous signaling network of chronic itch. mRNA profiles were generated by deep sequencing, in triplicate, using MGISEQ-2000. We found that both human keratinocytes and murine sensory neurons responded to IL-27 and BST2, resulting in enrichment of genes promoting itch and inflammation. IL-27-BST2 signaling pathway activation promotes cutaneous inflammation and itch, both leading into an aggravation of AD. This finding might help us to better understand the immune-neuro-modulatory mechanism in itch circuits

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE188242 | GEO | 2024/03/05

REPOSITORIES: GEO

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RNA-seq of primary human keratinocytes : Effects of IL-20 on gene expression

Project description:In the present study, RNA-seq were performed To explore biological significance of IL-20 in the neuro-cutaneous signaling network of chronic itch. mRNA profiles were generated by deep sequencing, in triplicate, using MGISEQ-2000. We found that human keratinocytes responded to IL-20, resulting in enrichment of genes promoting itch and inflammation. IL-20 activation promotes cutaneous inflammation and itch, both leading into an aggravation of AD. This finding might help us to better understand the immune-neuro-modulatory mechanism in itch circuits

2022-08-03 | GSE195538 | GEO

PLAUR-TLR2 Axis Promotes Chronic Itch

Project description:In the present study, RNA-seq were performed To identify clinical relevance of PLAUR, a putative Serpin E1 receptor, in cutaneous itch signaling and crosstalk pathways with other critical itch modulators.mRNA profiles were generated by deep sequencing, in triplicate, using MGISEQ-2000. Our experiment showed Serpin E1-treatment further led to a marked upregulation of TLR2 transcript in mDRG neurons, along with enhanced transcription of cosignaling proteins belonging to pro-inflammatory signaling pathways including NF-κB signaling proteins. We next investigated the consequence of TLR2 activation in mTGNs using the TLR agonists, Pam3CSK4 (TLR1/2 agonist), FSL-1 (TLR2/6 agonist), or vehicle. Among these transcripts, TLR2 was found upregulated strongest by both TLR2 agonists suggesting a selfenhancing feedback loop of TLR2 activation.The PLAUR-TLR2 axis promotes cutaneous inflammation and itch, both feeding into an aggravation of AD. This finding might help us to better understand the skin-nerve communication in itch circuits.

2022-08-03 | GSE189333 | GEO

RNA-seq of mouse tissue samples from animal model：Effects of MMP9 on gene expression.

Project description:In the present study, RNA-seq technique were performed To explore biological significance of MMP9 in the neuro-cutaneous signaling network of chronic itch. We used MMP-9-IN-1, a specific inhibitor of MMP9, or its vehicle to treat ACD model mice, and conducted high-throughput sequencing on ear tissue samples of mice. It was found that inhibition of MMP9 expression affected the expression of a variety of itching factors and skin inflammatory factors related to the skin pathology of chronic dermatitis. These changes may indicate that MMP9 is closely related to inflammation and pruritus. This finding might help us to better understand the immune-neuro-modulatory mechanism in itch circuits.

2024-02-13 | GSE232349 | GEO

IL-33-activated calcitonin gene-related peptide-producing memory Th2 cells co-operate with somatosensory neurons to induce conjunctival itch

Project description:Allergic conjunctivitis is a chronic inflammatory disease that is characterized by severe itch in the conjunctiva; but how neuro-immune interactions shape the pathogenesis of severe itch remains unclear. We identified a subset of memory-type pathogenic Th2 cells that preferentially expressed Il1rl1-encoding ST2 and Calca-encoding calcitonin gene-related peptide (CGRP) in the inflammatory conjunctiva using a single-cell analysis. The IL-33-ST2 axis in memory Th2 cells controlled the axonal elongation of the peripheral sensory C-fiber and the induction of severe itch. Pharmacological blockade and genetic deletion of CGRP signaling in vivo attenuated scratching behavior. The analysis of giant papillae from patients with severe allergic conjunctivitis revealed ectopic lymphoid structure formation with the accumulation of IL-33-producing epithelial cells and CGRP-producing pathogenic CD4+ T cells accompanied by peripheral nerve elongation. Thus, the IL-33-ST2-CGRP axis directs severe itch with neuro-reconstruction in the inflammatory conjunctiva and is a potential therapeutic target for severe itch in allergic conjunctivitis.

2022-05-20 | GSE203217 | GEO

Genome-wide mRNA expression profiling for Wild Type and Itch-/- Skin Transcriptomes by RNA sequencing

Project description:To test the hypothesis that defects in the termination of inflammatory signaling led to skin inflammation that results in the “Itchy” phenotype, we isolated RNA from the lesional skin of Itch-/- mice and from the skin of wild-type mice and performed genome-wide mRNA expression profiling by RNA sequencing. We ranked genes based on the fold change in their expression (increased or decreased) in Itch-/- skin relative to that in wild-type skin. The expression of several TNF–induced genes were increased in Itch-/- skin, including, IL-1?, IL-6, IL-11, IL-19, IL-1RL1, CCL4, CXCL3, CXCL2, CCL3, and CD14. mRNA profiles comparison between wild type (WT) skin and Itch-/- mice lesional skin

2015-03-04 | E-GEOD-65686 | biostudies-arrayexpress

Transcriptional regulation of human dorsal root ganglia cultures by type 2 cytokines

Project description:Cutaneous afferent neurons express receptors for type 2 cytokines, including interleukins (IL)-4, IL-13, and IL-33. These neuronal cytokine receptors were found to be required in several murine models of itch. The objective of the present study was to determine if type 2 cytokine stimulation sensitizes sensory neurons to future itch stimuli in a fully human ex vivo system. Human dorsal root ganglia were isolated and dissociated to establish ex vivo cultures and subjected to 24 hours of type 2 cytokine exposure with either vehicle, IL-4, IL-13, IL-33, or IL-4 and IL-13 together. After 24 hours, cells were harvested and RNA extracted and sequenced to determine the transcriptomic effects of type 2 cytokine exposure.

2023-09-22 | GSE242488 | GEO

Genome-wide mRNA expression profiling for Wild Type and Itch-/- Skin Transcriptomes by RNA sequencing

Project description:To test the hypothesis that defects in the termination of inflammatory signaling led to skin inflammation that results in the “Itchy” phenotype, we isolated RNA from the lesional skin of Itch-/- mice and from the skin of wild-type mice and performed genome-wide mRNA expression profiling by RNA sequencing. We ranked genes based on the fold change in their expression (increased or decreased) in Itch-/- skin relative to that in wild-type skin. The expression of several TNF–induced genes were increased in Itch-/- skin, including, IL-1β, IL-6, IL-11, IL-19, IL-1RL1, CCL4, CXCL3, CXCL2, CCL3, and CD14.

2015-03-04 | GSE65686 | GEO

Itch attenuates CD4 T cell proliferation in mice by limiting WBP2 protein stability

Project description:To mount an anti-pathogen response, CD4 T cells must undergo rapid cell proliferation. However, poorly controlled expansion can result in diseases such as autoimmunity. One important regulator of T cell activity is the E3 ubiquitin ligase Itch. Itch deficient patients suffer from extensive autoinflammation. Similarly, Itch deficient mice exhibit inflammation characterized by high numbers of activated CD4 T cells. While the role of Itch in limiting CD4 T cell cytokine production has been extensively studied, it is less clear whether and how Itch regulates proliferation of these cells. We determined that Itch deficient CD4 T cells are hyperproliferative in vitro and in vivo, due to increased S phase entry. Whole cell proteomics analysis of Itch deficient primary mouse CD4 T cells revealed increased abundance of the -catenin co-activator WW domain binding protein 2 (WBP2). Furthermore, Itch deficient cells demonstrate increased WBP2 protein stability, and Itch and WBP2 interact in CD4 T cells. Knockdown of WBP2 in CD4 T cells caused reduced proliferation. Together, our data support that Itch attenuates CD4 T cell proliferation by promoting WBP2 degradation. This study identifies novel roles for Itch and WBP2 in regulating CD4 T cell proliferation, providing insight into how Itch may prevent inflammation.

2021-01-07 | PXD019272 | Pride

Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses in autoimmune disorders

Project description:High levels of inflammation are often present in autoimmune diseases and can impact the functioning of the immune system. Specifically, how surrounding inflammation affects cytokine responses has not been extensively studied. We use IL-6 and IL-27, two cytokines playing opposite roles in inflammation, to ask how cytokines adapt to the inflammatory environment. We show that IL-27 induces a more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modelling of IL-6 and IL-27 signaling identify STAT1 (or STAT3) binding dynamics to GP130 (or IL-27R) as the main parameter contributing to sustained pSTAT1 by IL-27. Mutation of Tyr613 on IL-27R decreased IL-27-induced STAT1 phosphorylation by 80%, with limited effect on STAT3 phosphorylation. The strong receptor/STAT coupling by IL-27 led to the induction of a unique gene expression program by this cytokine, which required sustained STAT1 phosphorylation and IRF1 expression and was enriched in classical Interferon Stimulated Genes. Interestingly, the STAT/receptor coupling exhibited by IL-6/IL-27 was altered in Crohn’s disease and SLE patients. IL-6/IL-27 induced a more potent STAT1 activation in SLE patients than in healthy controls, which can be explained by the higher STAT1 expression in these patients. Partial inhibition of JAK activation by sub-saturating doses of Tofacitinib lowered the levels of STAT1 activation by IL-6, representing a new strategy to treat auto-immune disorders where cytokine responses are dysregulated.

2021-04-27 | GSE164479 | GEO

Single-cell RNA sequencing defines disease-specific differences between chronic nodular prurigo and atopic dermatitis

Project description:Background: Chronic nodular prurigo (CNPG) is a chronic inflammatory skin disease that is maintained by a chronic itch-scratch cycle likely rooted in neuro-immunological dysregulation. This condition may be associated with atopy in some patients, and there are now promising therapeutic results from blocking type-2 cytokines such as IL-4, IL-13 and IL-31. Nevertheless, underlying pathomechanisms as well as the molecular relationship with atopy remain ill-defined. Methods: We profiled skin lesions from patients with CNPG in comparison to atopic dermatitis (AD) and healthy control (HC) individuals using single-cell RNA sequencing combined with T-cell receptor sequencing. Results: We found type-2 immune skewing in both CNPG and AD, as evidenced by CD4+ helper T cells expressing IL13. However, only AD harbored an additional, oligoclonally expanded CD8A+ IL9R+ IL13+ cytotoxic T cell population, and immune activation pathways were highly upregulated in AD, but less so in CNPG. Conversely, CNPG showed signatures of extracellular matrix organization, collagen synthesis, and fibrosis, including a unique population of CXCL14- IL24+ secretory-papillary fibroblasts. Besides known itch mediators such as IL31 and oncostatin M (OSM), we also detected increased levels of neuromedin B (NMB) in fibroblasts of CNPG lesions compared to AD and HC, with NMB receptors detectable on some nerve endings. Conclusion: These data show that CNPG does not harbor the strong disease-specific immune activation pathways that are typically found in AD, but is rather characterized by upregulated stromal remodeling mechanisms that might directly impact itch fibers.

2023-05-24 | GSE222840 | GEO

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