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IL6R is a target of miR-197 in human keratinocytes

ABSTRACT: Background: Psoriasis is a chronic inflammatory disorder with cutaneous and systemic manifestations and substantial negative effects on patients' life quality. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Evidence suggests that miRNAs play a role in the pathogenesis of psoriasis. Previously studies, from others and by us, show-specific miRNAs that are differentially expressed between the psoriasis lesion and healthy skin. One of those miRNAs is miR-197-3p whose expression is down-regulated in the psoriatic lesions compared to normal or uninvolved psoriatic skin. In order to understand miR-197's role in psoriasis, we found that it could modulate IL-22 and IL-17 signaling. Objectives: We aimed to identify additional biochemical targets of miR-197 in psoriasis. Methods: We have chosen to apply a transcriptome-wide biochemical approach (PAR-CLIP) to search for new targets of miR-197 in keratinocytes. Results: in this work, using PAR-CLIP, we found an additional biochemical target of miR-197, one of the subunits of the receptor to IL-6. IL-6R is known to be up-regulated in psoriasis and even was considered as a possible therapeutic target. Conclusions: From the present data and our previous studies it appears that miR-197 is a major regulator of the interaction between immune system cells and keratinocytes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155538 | GEO | 2020/08/25

REPOSITORIES: GEO

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Project description:IL-20 cytokines are involved in the establishment of psoriasis, a common chronic skin inflammation epidemiologically associated with metabolic syndrome, but molecular mechanisms underlying their over-expression remain to be elucidated. We find that keratinocytes (KCs) expressed IL-20 and lymphocytes expressed IL-22 cytokines up-regulation occurs at post-transcriptional level with stabilization of their RNA messengers. Looking at psoriatic epidermis, we observe that the p38/MK2 pathway is not activated but that the RNA-binding protein (RBP) HuR re-localizes in keratinocytes cytoplasm, suggesting post-transcriptional regulation of numerous mRNAs. HuR ribonucleoprotein immunoprecipitations analyzed by high-throughput sequencing (RIP-Seq) identify potential pre-mature and mature RNA targets for uninvolved and involved skin and confirms that HuR activity is displaced from the nucleus to the cytoplasm. Numerous psoriasis up-regulated transcripts are HuR targets and HuR knockdown reduces expression of transcripts like beta-defensin-2, CXCL-10 or IL-2, suggesting an implication of HuR in pathophysiological processes such as morphological, immune and metabolic inflammatory responses. Finally, metabolic disorders affecting psoriatic keratinocytes are responsible for HuR cytoplasmic localization since a decreased activity of the cellular metabolic sensor AMPK, that is observed in human psoriatic epidermis, is sufficient to promote HuR cytosolic localization as well as IL-20 over-production both in human keratinocytes and in vivo in mouse epidermis where it then initiates psoriasis-like histological changes. These results may provide insights into molecular links between metabolism and post-transcriptional networks during chronic inflammation, as illustrated in psoriasis by mechanisms connecting AMPK, HuR and IL-20. Analysis of HuR-binding RNA in uninvolved versus involved psoriatic samples by RIP-Seq. Samples from five different patients were used for both uninvolved and involved skin. RIP-Seq was also made using a control IgG.

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IL6R is a target of miR-197 in human keratinocytes

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