Decreased A-to-I RNA editing as a source of keratinocytes' dsRNA in psoriasis

Shallev, Lea; Kopel, Eli; Feiglin, Ariel; Leichner, Gil S.; Avni, Dror; Sidi, Yechezkel; Eisenberg, Eli; Barzilai, Aviv; Levanon, Erez Y.; Greenberger, Shoshana

doi:10.1261/rna.064659.117

Cited by 35 publications

(32 citation statements)

References 80 publications

(101 reference statements)

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“…An antiviral response in psoriasis was investigated by Raposo et al, who provided evidence for reduced RNA editing activity in lesional skin. This decrease in adenosine-to-inosine editing entails an accumulation of unwinded dsRNA in keratinocytes with downstream activation of the MDA5/MAVs pathway [79]. In line with this, dsRNA pattern recognition sensors were shown to be upregulated in psoriasis [80].…”

Section: Psoriasismentioning

confidence: 74%

“…In addition, anti-TNFα treatment led to the upregulation of VEGF negative regulating pathways [179]. Notably, the markedly diminished RNA editing functionality in lesional skin was not observed in non-lesional skin [79]. Skin tissue-resident T memory cells (Trm) are thought to contribute to the underlying mechanism of a consistent pre-psoriatic skin state.…”

Section: Dcsmentioning

confidence: 99%

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Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

Schwingen

Kaplan

Kurschus

2020

IJMS

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During the last decades, high-throughput assessment of gene expression in patient tissues using microarray technology or RNA-Seq took center stage in clinical research. Insights into the diversity and frequency of transcripts in healthy and diseased conditions provide valuable information on the cellular status in the respective tissues. Growing with the technique, the bioinformatic analysis toolkit reveals biologically relevant pathways which assist in understanding basic pathophysiological mechanisms. Conventional classification systems of inflammatory skin diseases rely on descriptive assessments by pathologists. In contrast to this, molecular profiling may uncover previously unknown disease classifying features. Thereby, treatments and prognostics of patients may be improved. Furthermore, disease models in basic research in comparison to the human disease can be directly validated. The aim of this article is not only to provide the reader with information on the opportunities of these techniques, but to outline potential pitfalls and technical limitations as well. Major published findings are briefly discussed to provide a broad overview on the current findings in transcriptomics in inflammatory skin diseases.

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Section: Psoriasismentioning

confidence: 74%

Section: Dcsmentioning

confidence: 99%

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

Schwingen

Kaplan

Kurschus

2020

IJMS

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“…Further, ADAR1 and especially its isoform ADAR1p150 is a type I interferon-inducible gene [ 28 ]. Accordingly, ADAR1 expression was found to be increased in type I interferon-associated autoimmune diseases [ [34] , [35] , [36] , [37] , [38] , [39] ], but also in other inflammatory diseases including acute myocardial infarction, atherosclerosis, cancer and viral infections [ 14 , 40 , 41 ]. More importantly, ADAR1 expression and activity are increased after stimulation with TNFα [ 14 ], the major cytokine that regulates the dynamics of transcriptome in RA [ 42 ], due to a significant increase in levels of ADAR1p150 isoform [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Increased adenosine-to-inosine RNA editing in rheumatoid arthritis

Vlachogiannis

Gatsiou

Silvestris

et al. 2020

Journal of Autoimmunity

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Objective Adenosine-to-inosine (A-to-I) RNA editing of Alu retroelements is a primate-specific mechanism mediated by adenosine deaminases acting on RNA (ADARs) that diversifies transcriptome by changing selected nucleotides in RNA molecules. We tested the hypothesis that A-to-I RNA editing is altered in rheumatoid arthritis (RA). Methods Synovium expression analysis of ADAR1 was investigated in 152 RA patients and 50 controls. Peripheral blood mononuclear cells derived from 14 healthy subjects and 19 patients with active RA at baseline and after 12-week treatment were examined for ADAR1p150 and ADAR1p110 isoform expression by RT-qPCR. RNA editing activity was analysed by AluSx + Sanger-sequencing of cathepsin S, an extracellular matrix degradation enzyme involved in antigen presentation. Results ADAR1 was significantly over-expressed in RA synovium regardless of disease duration. Similarly, ADAR1p150 isoform expression was significantly increased in the blood of active RA patients. Individual nucleotide analysis revealed that A-to-I RNA editing rate was also significantly increased in RA patients. Both baseline ADAR1p150 expression and individual adenosine RNA editing rate of cathepsin S AluSx + decreased after treatment only in those patients with good clinical response. Upregulation of the expression and/or activity of the RNA editing machinery were associated with a higher expression of edited Alu -enriched genes including cathepsin S and TNF receptor-associated factors 1,2,3 and 5. Conclusion A previously unrecognized regulation and role of ADAR1p150-mediated A-to-I RNA editing in post-transcriptional control in RA underpins therapeutic response and fuels inflammatory gene expression, thus representing an interesting therapeutic target.

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“…It has been recently demonstrated that inflammatory phenotype of psoriasis can be induced by excessive cytokine production by keratinocytes in response to both external and endogenous triggers . The damage‐associated molecular patterns (DAMPs) such as DNA or RNA derived from necrotic cells could activate keratinocytes . We previously reported that double‐stranded RNA (dsRNA) released from necrotic keratinocytes stimulated the upregulation of ICAM‐1 and proinflammatory cytokines in human melanocytes .…”

Section: Introductionmentioning

confidence: 99%

IL‐17A synergistically enhances TLR3‐mediated IL‐36γ production by keratinocytes: A potential role in injury‐amplified psoriatic inflammation

Liu

et al. 2019

Experimental Dermatology

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Skin injury can trigger formation of new lesions in psoriasis (Koebner phenomenon). The mechanisms through which injury exacerbates psoriasis are unclear. During wound repair, epidermal keratinocytes are activated and produce abundant IL‐36γ, further promoting the skin inflammation. IL‐17A is the cornerstone cytokine in the pathogenesis of psoriasis. We sought to investigate the effects of IL‐17A on injury‐induced keratinocyte activation and IL‐36γ production. Here, we demonstrated that dsRNA released from necrotic keratinocytes induced the expression of IL‐36γ. Silencing of TLR3 by siRNA decreased the IL‐36γ induction by necrotic keratinocyte supernatant. Co‐stimulation with dsRNA and IL‐17A synergistically increased the expression of IL‐36γ and other proinflammatory mediators (CCL20, CXCL8, DEFB4 and LCN2) in keratinocytes. The synergistic effects were not dependent on TLR3 upregulation, TNF receptor signalling and mRNA stabilization. Co‐stimulation with dsRNA and IL‐17A resulted in an accumulation of IκBζ. The synergistic upregulation of IL‐36γ and proinflammatory mediators were inhibited by IκBζ siRNA. Co‐stimulation with IL‐17A and poly(I:C) markedly activated the p38 MAPK and NF‐κB pathway, compared with poly(I:C). Blockade of p38 MAPK and NF‐κB suppressed dsRNA/IL‐17A–mediated IκBζ and IL‐36γ induction. These findings demonstrated that IL‐17A synergistically enhanced the dsRNA‐mediated IL‐36γ production through a p38 MAPK‐, NF‐κB–, and IκBζ‐dependent mechanism.

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Decreased A-to-I RNA editing as a source of keratinocytes' dsRNA in psoriasis

Cited by 35 publications

References 80 publications

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

Increased adenosine-to-inosine RNA editing in rheumatoid arthritis

IL‐17A synergistically enhances TLR3‐mediated IL‐36γ production by keratinocytes: A potential role in injury‐amplified psoriatic inflammation

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