Laser capture microdissection followed by next‐generation sequencing identifies disease‐related micro<scp>RNA</scp>s in psoriatic skin that reflect systemic micro<scp>RNA</scp> changes in psoriasis

Løvendorf, Marianne B.; Mitsui, Hiroshi; Zibert, John R.; Røpke, Mads A.; Hafner, Markus; Dyring‐Andersen, Beatrice; Bonefeld, Charlotte M.; Krueger, James G.; Skov, Lone

doi:10.1111/exd.12604

Cited by 70 publications

(93 citation statements)

References 51 publications

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“…Previous miRNA profiling studies have suggested increased expression of miR-146a/b in lesional skin of psoriasis patients (Lovendorf et al , 2015; Sonkoly et al , 2007). First, we confirmed by RT-qPCR that miR-146a/b are more highly expressed in lesional as compared to non-lesional skin of psoriasis patients and the skin of control individuals (Figure 1a, Supplementary Table S1), however, no correlation with psoriasis severity was found (see Supplementary Figure S1 online).…”

Section: Resultsmentioning

confidence: 97%

“…Previous miRNA profiling studies suggested that the expression of miR-146a/b is increased in the lesional skin of psoriasis patients (Lovendorf et al , 2015; Sonkoly et al , 2007). We confirmed this result and demonstrated that miR-146a level is elevated in the epidermis and in less extent in the dermis of psoriatic skin, while miR-146b is increased in both the epidermis and the dermis.…”

Section: Discussionmentioning

confidence: 99%

“…Mature miR-146a/b differ from each other in only two nucleotides, which suggests that they target very similar sets of transcripts (Taganov et al , 2006). Both miR-146a/b have been shown to be upregulated in the skin of psoriasis patients (Lovendorf et al , 2015; Sonkoly et al , 2007). Numerous studies demonstrate that miR-146a has an anti-inflammatory function.…”

Section: Introductionmentioning

confidence: 99%

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miR-146b Probably Assists miRNA-146a in the Suppression of Keratinocyte Proliferation and Inflammatory Responses in Psoriasis

Hermann

Runnel

Aab

et al. 2017

Journal of Investigative Dermatology

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miR-146a inhibits inflammatory responses in human keratinocytes and in different mouse models of skin inflammation. Little is known about the role of miR-146b in the skin. In the present study, we confirmed the increased expression of miR-146a and miR-146b (miR-146a/b) in lesional skin of psoriasis patients. The expression of miR-146a was about 2-fold higher than that of miR-146b in healthy human skin and it was more strongly induced by stimulation of pro-inflammatory cytokines in keratinocytes and fibroblasts. miR-146a/b target genes regulating inflammatory responses or proliferation were altered in the skin of psoriasis patients, among which FERMT1 was verified as direct target of miR-146a. In silico analysis of genome-wide data from >4,000 psoriasis cases and >8,000 controls confirmed a moderate association between psoriasis and genetic variants in miR-146a gene. Transfection of miR-146a/b suppressed and inhibition enhanced keratinocyte proliferation and the expression of psoriasis-related target genes. Enhanced expression of miR-146a/b-influenced genes was detected in cultured keratinocytes from miR-146a−/− and skin fibroblasts from miR-146a−/− and miR-146b−/− mice stimulated with psoriasis-associated cytokines as compared to wild type mice. Our results indicate that besides miR-146a, miR-146b is expressed and might be capable of modulation of inflammatory responses and keratinocyte proliferation in psoriatic skin.

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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miR-146b Probably Assists miRNA-146a in the Suppression of Keratinocyte Proliferation and Inflammatory Responses in Psoriasis

Hermann

Runnel

Aab

et al. 2017

Journal of Investigative Dermatology

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“…Although they do not encode proteins, microRNAs may also play a role in the immunogenetics of psoriasis [113, 114]. The rs2910164 SNP of miR-146a was associated with an increased risk of psoriasis in one study [115].…”

Section: Immune Genes With Less-well Established Links To Psoriasimentioning

confidence: 99%

The immunogenetics of Psoriasis: A comprehensive review

Harden

Krueger

Bowcock

2015

Journal of Autoimmunity

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524

401

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Psoriasis vulgaris is a common, chronic inflammatory skin disease with a complex etiology involving genetic risk factors and environmental triggers. Here we describe the many known genetic predispositions of psoriasis with respect to immune genes and their encoded pathways in psoriasis susceptibility. These genes span an array of functions that involve antigen presentation (HLA-Cw6, ERAP1, ERAP2, MICA), the IL-23 axis (IL12Bp40, IL23Ap19, IL23R, JAK2, TYK2), T-cell development and T-cells polarization (RUNX1, RUNX3, STAT3, TAGAP, IL4, IL13), innate immunity (CARD14, c-REL, TRAF3IP2, DDX58, IFIH1), and negative regulators of immune responses (TNIP1, TNFAIP3, NFKBIA, ZC3H12C, IL36RN, SOCS1). The contribution of some of these gene products to psoriatic disease has also been revealed in recent years through targeting of key immune components, such as the Th17/IL-23 axis which has been highly successful in disease treatment. However, many of the genetic findings involve immune genes with less clear roles in psoriasis pathogenesis. This is particularly the case for those genes involved in innate immunity and negative regulation of immune specific pathways. It is possible that risk alleles of these genes decrease the threshold for the initial activation of the innate immune response. This could then lead to the onslaught of the pathogenic adaptive immune response known to be active in psoriatic skin. However, precisely how these various genes affect immunobiology need to be determined and some are speculated upon in this review. These novel genetic findings also open opportunities to explore novel therapeutic targets and potentially the development of personalized medicine, as well as discover new biology of human skin disease.

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“…It is tempting to speculate that aberrant epigenetic silencing of the miR-197 promoter underlies its decreased expression in psoriasis. The mechanism leading to miR-197 silencing, as well to additional alterations in miRNAs in the psoriatic lesion [25,26,50,51], should be further investigated. Study of the epigenetic structure of miR-197 and its putative promoter sequences in the psoriatic genome might partially answer this question.…”

Section: Discussionmentioning

confidence: 99%

Positive-Negative Feedback Loop between Mir-197 and IL-17A Signaling in Human Keratinocytes

Elharrar¹,

Masalha²,

Lerman³

et al. 2016

Immunome Res

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Psoriasis is a chronic inflammatory skin disorder which results from pathological interactions between activated immunocytes and keratinocytes. Recent studies implicated the role of IL-17 and IL-22, secreted from Th17 and Th22 in the generation and propagation of the psoriatic plaque. Previously, we and others have shown that the expression of miR-197 is significantly decreased in psoriatic lesions. We further showed that miR-197 targets IL-22RA1 and that ectopic expression of miR-197 prevent IL-22 induced proliferation and migration of keratinocytes.Since the 3'UTR of the IL17RA subunit mRNA contains a putative binding site for miR-197, our aim was to expand our understanding of the miRNA-mediated crosstalk between immunocytes and keratinocytes by studying the effect of miR-197 expression on IL-17A signaling pathway. Luciferase reporter assays along with Western blot analysis revealed that miR-197 directly targets the 3'UTR of IL17RA. Furthermore, ectopic expression of miR-197 led to a significant decrease in IL-17A-induced expression of CCL20, a known downstream effector of IL-17A. Interestingly, the addition of IL-17A to keratinocytes led to a rapid and transient increase in the expression of miR-197. Chromatin immuno-precipitation assays showed that keratinocytes' treatment with IL-17 leads to C/EBP binding to the promoter region of miR-197, and that the expression level of miR-197 is directly proportional to the extent of C/EBP binding to the promoter. Moreover, following treatment with IL-17A, the histone acetylation pattern at the miR-197 promoter turns to become characteristic of transcribed chromatin.Taken together, our results suggest that a positive-negative feedback loop exists between IL-17A and miR-197 in keratinocytes; the cytokine induces the binding of C/EBPα to miR-197 promoter sequences, enhances miR-197 expression that negatively attenuates IL-17 receptor and decreases the input along the IL-17A pathway. Our work suggests that in psoriasis, decreased expression of miR-197 may prevent the miR-197-induced attenuation of the IL-17 cascade, leading to its over-activity.

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Laser capture microdissection followed by next‐generation sequencing identifies disease‐related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis

Cited by 70 publications

References 51 publications

miR-146b Probably Assists miRNA-146a in the Suppression of Keratinocyte Proliferation and Inflammatory Responses in Psoriasis

miR-146b Probably Assists miRNA-146a in the Suppression of Keratinocyte Proliferation and Inflammatory Responses in Psoriasis

The immunogenetics of Psoriasis: A comprehensive review

Positive-Negative Feedback Loop between Mir-197 and IL-17A Signaling in Human Keratinocytes

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