Cathelicidin LL-37-induced transcriptome of human keratinocyte identifies chemokine CXCL10 link to T cell-mediated rosacea pathogenesis via JAK-1/STAT-1 pathway
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ABSTRACT:
PROVIDER: PRJNA1294752 | ENA |
REPOSITORIES: ENA
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Project description:Rosacea is a chronic inflammatory disease of facial skin with unknown pathophysiology. Abnormal overexpression of human antimicrobial peptide LL-37 is a hallmark of rosacea. However, its significance in the rosacea pathogenesis is not fully understood. We sought to understand the molecular mechanisms of LL-37-mediated rosacea-like inflammation in an in-vitro model of normal human epidermal keratinocytes. Transcriptome profiling of LL-37-treated keratinocytes identified signatures of interferon (IFN)-stimulating genes (ISGs) such as CXCL10, IFIT2, RSAD2 and CXCL11 among the top upregulated differentially expressed genes. Gene ontogeny (GO) enrichment of biological processes revealed activation of cellular response to molecules of bacterial origin, response to chemokines, and cytokine mediated signaling pathways. While KEGG enrichment analysis revealed the activation of TNF signaling, IL-17 signaling, NF-kB signaling and chemokine signaling among the most significant pathways. Remarkably, T cell recruiting chemokine CXCL10 turns out to be the most abundant inflammatory mediator overexpressed upon LL-37 exposure. Mechanistically, LL-37 induced CXCL10 production relied on JAK-1/STAT-1 signaling pathway. In summary, our findings provide a crucial link to keratinocyte: T cell crosstalk and blockade of CXCL10:CXCR3 axis or JAK-1/STAT-1 pathways can be an effective anti-inflammatory strategy to reduce rosacea inflammation by restricting pathogenic T cells infiltration.
2025-07-22 | GSE303282 | GEO
Project description:The goal of this study is to figure out the role of mTORC1 signaling in the pathogenesis of rosacea by comparing rosacea mouse model skin lesion transcriptome profiling (RNA-seq) to that of control mouse skin treated with or without rapamycin.
2021-02-08 | GSE147950 | GEO
Project description:Rosacea is a common chronic inflammatory skin disease of unknown etiology. Our knowledge about an involvement of the adaptive immune system is very limited. We performed detailed transcriptome analysis, qRT-PCR, and quantitative immunohistochemistry on facial biopsies of rosacea patients, classified according to their clinical subtype. As controls, we used samples from healthy controls. Our study shows significant activation of the immune system in all subtypes of rosacea, characterizing erythematotelangiectatic rosacea (ETR) already as a disease with significant influx of proinflammatory cells. The T cell response is dominated by Th1/Th17-polarized immune cells, as demonstrated by significant upregulation of IFNγ or IL-17, for example. Chemokine expression patterns support a Th1/Th17 polarization profile of the T cell response. Macrophages and mast cells are increased in all three subtypes of rosacea, while neutrophils reach a maximum in papulopustular rosacea. Our studies also provide evidence for activation of plasma cells with significant antibody production already in ETR, followed by a crescendo pattern towards phymatous rosacea. In sum, Th1/Th17 polarized inflammation and macrophage infiltration is an underestimated hallmark in all subtypes of rosacea. Therapies directly targeting the Th1/Th17 pathway are promising candidates in the future treatment of this skin disease.
2015-06-01 | GSE65914 | GEO
Project description:Rosacea is a common chronic inflammatory skin disease of unknown etiology. Our knowledge about an involvement of the adaptive immune system is very limited. We performed detailed transcriptome analysis, qRT-PCR, and quantitative immunohistochemistry on facial biopsies of rosacea patients, classified according to their clinical subtype. As controls, we used samples from healthy controls. Our study shows significant activation of the immune system in all subtypes of rosacea, characterizing erythematotelangiectatic rosacea (ETR) already as a disease with significant influx of proinflammatory cells. The T cell response is dominated by Th1/Th17-polarized immune cells, as demonstrated by significant upregulation of IFNγ or IL-17, for example. Chemokine expression patterns support a Th1/Th17 polarization profile of the T cell response. Macrophages and mast cells are increased in all three subtypes of rosacea, while neutrophils reach a maximum in papulopustular rosacea. Our studies also provide evidence for activation of plasma cells with significant antibody production already in ETR, followed by a crescendo pattern towards phymatous rosacea. In sum, Th1/Th17 polarized inflammation and macrophage infiltration is an underestimated hallmark in all subtypes of rosacea. Therapies directly targeting the Th1/Th17 pathway are promising candidates in the future treatment of this skin disease. Total of 58 chips. 19 patients and 10 healthy volunteers
2015-06-01 | E-GEOD-65914 | biostudies-arrayexpress
Project description:A positive feedback circuit between mTORC1 signaling and cathelicidin promotes skin inflammation in rosacea [mouse]
| PRJNA622593 | ENA
Project description:CXCL10 is a chemokine induced by IFN-γ and implicated in the pathogenesis of type 1 diabetes (T1D). It attracts IFN-γ-producing T cells to the pancreatic islets, forming a positive feed-forward loop where T cells induce CXCL10 and attract themselves, but it is unclear what attracts the first IFN-γ-producing T cells in islets. Lipopolysaccharide induced CXCL10 production in cultured islets of nonobese diabetic (NOD) mice, and the lack of its inhibition in islets from NOD mice deficient for RAG1 or IFN-g receptor revealed its dissociation from the requirement of T cells and IFN-γ. To further investigate the mechanism of LPS induced CXCL10 production, the gene expression profile of pancreatic beta cells after culture of whole islets in LPS was analysed. Overall a gene expression signature of cytokine signalling, particularly by type I IFNs and TLR4 was upregulated after culture of islets in LPS.
2023-03-07 | GSE218698 | GEO
Project description:Cathelicidin LL-37 is a multifunctional immunomodulatory and antimicrobial host defense peptide that has an important role in the immune defenses of the skin and other epithelial barriers. We have previously demonstrated that at physiological concentrations LL-37 synergistically augments the production of immune mediators in response to microbial compounds in human primary keratinocytes. Here we define the signaling mechanisms responsible for this activity. We demonstrate that inhibition of Src family kinases (SFKs) strongly inhibited the synergistic chemokine production in response to LL-37 and flagellin in keratinocytes. SFK activation was induced by LL-37 stimulation and was required for the downstream activation of Akt (protein kinase B) and the transcription factors CREB and ATF1. In cells stimulated with LL-37 and flagellin together, Akt activation was primarily induced by LL-37, while both flagellin and LL-37 contributed to the activation of CREB and ATF1 and consequently chemokine induction. The purinergic receptor P2X₇ was identified as the receptor upstream of SFK activation in LL-37-stimulated keratinocytes. Overall, these findings established the P2X₇-SFK-Akt-CREB/ATF1 signaling pathway activated by LL-37 in primary keratinocytes. These signaling mechanisms mediated the synergistic effects of LL-37 on chemokine production in flagellin-stimulated keratinocytes, and thus might have a role in the immune defenses of the skin and possibly other epithelial barriers.
| S-EPMC6741628 | biostudies-literature
Project description:The goal of this study is to utilize human papulopustular rosacea biopsy explants to integrate both differentially expressed genes and differently expressed proteins in paired non-lesional and lesional papulopustular rosacea tissues. Methods: mRNA profiles from non-lesional and lesional papulopustular rosacea human skins were generated by deep sequencing, in duplicate using Illumina system. Proteomic profiles were also investigated using both the MSD and the OLINK proteomic platforms. Conclusions: Our study suggests that MAPK and TNF signaling pathways are the most significantly upregulated pathways in lesional papulopustular rosacea human skins, highlighting IL-1β as a potential central mediator.
2021-05-06 | GSE155141 | GEO
Project description:LPS induced CXCL10 chemokine production via IFN- α receptor and toll-like receptor 4 signalling
| PRJNA904908 | ENA