| 1. |
- Luo, Longlong, et al.
(författare)
-
The Long Noncoding RNA LINC00958 Is Induced in Psoriasis Epidermis and Modulates Epidermal Proliferation
- 2023
-
Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 143:6, s. 999-1010
-
Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is a common, immune-mediated skin disease characterized by epidermal hyperproliferation and chronic skin inflammation. Long noncoding RNAs are >200 nucleotide-long transcripts that possess important regulatory functions. To date, little is known about the contribution of long noncoding RNAs to psoriasis. In this study, we identify LINC00958 as a long noncoding RNA overexpressed in keratinocytes (KCs) from psoriasis skin lesions, in a transcriptomic screen performed on KCs sorted from psoriasis and healthy skin. Increased levels of LINC00958 in psoriasis KCs were confirmed by RT-qPCR and single-molecule in situ hybridization. Confocal microscopy and analysis of subcellular fractions showed that LINC00958 is mainly localized in the cytoplasm of KCs. IL-17A, a key psoriasis cytokine, induced LINC00958 in KCs through C/EBP-β and the p38 pathway. The inhibition of LINC00958 led to decreased proliferation as measured by Ki-67 expression, live cell analysis imaging, and 5-ethynyl-2-deoxyuridine assays. Transcriptomic analysis of LINC00958-depleted KCs revealed enrichment of proliferation- and cell cycle‒related genes among differentially expressed transcripts. Moreover, LINC00958 depletion led to decreased basal and IL-17A‒induced phosphorylation of p38. Furthermore, IL-17A‒induced KC proliferation was counteracted by the inhibition of LINC00958. In summary, our data support a role for the IL-17A‒induced long noncoding RNA, LINC00958, in the pathological circuits of psoriasis by reinforcing IL-17A‒induced epidermal hyperproliferation.
|
|
| 2. |
- Martinez Sanchez, Alvaro, et al.
(författare)
-
Causality analysis of large-scale structures in the flow around a wall-mounted square cylinder
- 2023
-
Ingår i: Journal of Fluid Mechanics. - : Cambridge University Press (CUP). - 0022-1120 .- 1469-7645. ; 967
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this work is to analyse the formation mechanisms of large-scale coherent structures in the flow around a wall-mounted square cylinder, due to their impact on pollutant transport within cities. To this end, we assess causal relations between the modes of a reduced-order model obtained by applying proper orthogonal decomposition to high-fidelity simulation data of the flow case under study. The causal relations are identified using conditional transfer entropy, which is an information-theoretical quantity that estimates the amount of information contained in the past of one variable about another. This allows for an understanding of the origins and evolution of different phenomena in the flow, with the aim of identifying the modes responsible for the formation of the main vortical structures. Our approach unveils that vortex-breaker modes are the most causal modes, in particular, over higher-order modes, and no significant causal relationships were found for vortex-generator modes. We validate this technique by determining the causal relations present in the nine-equation model of near-wall turbulence developed by Moehlis et al. (New J. Phys., vol. 6, 2004, p. 56), which are in good agreement with literature results for turbulent channel flows.
|
|
| 3. |
- Padhi, Avinash, et al.
(författare)
-
IL-22 Downregulates Peptidylarginine Deiminase-1 in Human Keratinocytes : Adding Another Piece to the IL-22 Puzzle in Epidermal Barrier Formation
- 2022
-
Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 142:2, s. 333-342.e6
-
Tidskriftsartikel (refereegranskat)abstract
- Increased presence of IL-22(+) cells in the skin is a characteristic finding in skin barrier defects, such as psoriasis and atopic dermatitis. However, mechanistic insight into effects of IL-22 on epidermal functioning is yet to be elucidated. One crucial step during epidermal differentiation is deimination or citrullination. Here, we show reduced levels of peptidylarginine deiminase 1, an enzyme that converts peptidylarginine into citrulline in lesional psoriatic skin. IL-22 signaling through the IL-22 receptor complex was found to suppress expression of peptidylarginine deiminase 1 in epidermal keratinocytes. Subsequently, total peptidylarginine deiminase activity and extent of protein deimination in keratinocytes treated with IL-22 were reduced together with a significant decrease in deimination of keratin 1 and FLG, both important for epidermal differentiation. Vitamin D and acitretin partly restored the peptidylarginine deiminase 1 defect caused by IL-22. Collectively, we show that IL-22 downregulates deimination, thus identifying a potential target for treatment of skin barrier defects.
|
|
| 4. |
- Pasquali, Lorenzo, et al.
(författare)
-
The Keratinocyte Transcriptome in Psoriasis : Pathways Related to Immune Responses, Cell Cycle and Keratinization.
- 2019
-
Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 0001-5555 .- 1651-2057. ; 99:2, s. 196-205
-
Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is a common immune-mediated disease resulting from altered cross-talk between keratinocytes and immune cells. Previous transcriptomic studies have identified thousands of deregulated genes in psoriasis skin; however, the transcriptomic changes confined to the epidermal compartment remained poorly characterized. The aim of this study was to characterize the transcriptomic landscape of psoriatic keratinocytes, using sorted CD45neg epidermal cells. Genes with functions in innate immunity, type I interferon response, cell cycle and keratinization were enriched among deregulated genes in psoriatic keratinocytes. Gene set enrichment analysis indicated the dominance of interleukin (IL)-22/IL-17A signatures in the epidermal psoriasis-signature. A set of deregulated genes overlapped with psoriasis-associated genetic regions, suggesting that genetic variations affecting gene expression in keratinocytes contribute to susceptibility to psoriasis. Several psoriasis-susceptibility genes, which were previously believed to be expressed preferentially or exclusively in immune cells, were identified as having altered expression in psoriatic keratinocytes. These results highlight the role of keratinocytes in the pathogenesis of psoriasis, and indicate that both genetic factors and an inflammatory microenvironment contribute to epidermal alterations in psoriasis.
|
|
| 5. |
- Srivastava, Ankit, et al.
(författare)
-
Cross-talk between IFN-γ and TWEAK through miR-149 amplifies skin inflammation in psoriasis
- 2021
-
Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 147:6, s. 2225-2235
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Psoriasis is a chronic inflammatory skin disease with disturbed interplay between immune cells and keratinocytes. A strong IFN-γ signature is characteristic for psoriasis skin, but the role of IFN-γ has been elusive. MicroRNAs are short RNAs regulating gene expression.OBJECTIVE: Our aim was to investigate the role of miR-149 in psoriasis and in the inflammatory responses of keratinocytes.METHODS: miR-149 expression was measured by quantitative RT-PCR in keratinocytes isolated from healthy skin and lesional and nonlesional psoriasis skin. Synthetic miR-149 was injected intradermally into the back skin of mice, and imiquimod was applied to induce psoriasis-like skin inflammation, which was then evaluated at the morphologic, histologic, and molecular levels. miR-149 was transiently overexpressed or inhibited in keratinocytes in combination with IFN-γ- and/or TNF-related weak inducer of apoptosis (TWEAK)-treatment.RESULTS: Here we report a microRNA-mediated mechanism by which IFN-γ primes keratinocytes to inflammatory stimuli. Treatment with IFN-γ results in a rapid and long-lasting suppression of miR-149 in keratinocytes. Depletion of miR-149 in keratinocytes leads to widespread transcriptomic changes and induction of inflammatory mediators with enrichment of the TWEAK pathway. We show that IFN-γ-mediated suppression of miR-149 leads to amplified inflammatory responses to TWEAK. TWEAK receptor (TWEAKR/Fn14) is identified as a novel direct target of miR-149. The in vivo relevance of this pathway is supported by decreased miR-149 expression in psoriasis keratinocytes, as well as by the protective effect of synthetic miR-149 in the imiquimod-induced mouse model of psoriasis.CONCLUSION: Our data define a new mechanism, in which IFN-γ primes keratinocytes for TWEAK-induced inflammatory responses through suppression of miR-149, promoting skin inflammation.
|
|
| 6. |
- Srivastava, Ankit
(författare)
-
Gene regulation in psoriatic keratinocytes : microRNAs and cytokine responses
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Psoriasis is the most common chronic skin inflammation in adults which affects 2-4% of the world population. Keratinocytes are the key structural cells in epidermis which hyper-proliferate and undergo aberrant differentiation in psoriasis. Keratinocyte-derived cytokines and chemokines are essential in maintaining the vicious auto-inflammatory loop in psoriasis. MicroRNAs (miRNAs) are small RNAs (22-25 nucleotides) which regulates gene expression at the post-transcriptional level. In this thesis, we explored the functional role of miRNAs/ cytokine networks in psoriasis. Paper I: A strong protective association of SNP (rs2910164-CC) of miR-146a to early onset of psoriasis was observed in HLA-C*06-negative patients. In addition, miR-146a deletion in mice led to earlier onset, more severe inflammation and impaired healing of imiquimod-induced psoriasis-like skin inflammation. Therapeutically, miR-146a mimic injection prevented psoriasiform skin-inflammation in WT mice, suggesting an anti-inflammatory role of miR-146a. Paper II: Here we explored the landscape of miRNAs in psoriatic keratinocytes. We identified several miRNAs, which were not identified in psoriasis before and their expression was altered in keratinocyte. In addition, upregulation of miR-1307-3p and human-specific miR-941 was validated with qRT-PCR. Paper III: MiR-149 was found to be downregulated in psoriatic keratinocytes compared to keratinocytes from non-lesional or healthy skin. In vitro studies revealed that the downregulation of miR-149 is mediated by IFN-γ/JAK/STAT axis. Functionally, miR-149 targeted the inflammatory and JAK/STAT pathway genes in resting as well as in IFN-γ treated keratinocytes. Moreover, miR-149 inhibition potentiated IFN-γ responses in keratinocytes. Paper IV: Here we outlined a new mode of action of tofactinib, a JAK inhibitor with effects on psoriasis in clinical trials. We showed that JAK proteins that are targets of tofacitinib are expressed by keratinocytes and tofacitinib had a robust impact on IL-22- regulated transcriptome in keratinocytes. Our results imply that effects of tofacitinib are not just limited to T-cells as previously thought but can also be observed in keratinocytes.
|
|
| 7. |
- Srivastava, Ankit, et al.
(författare)
-
Identification of chronological and photoageing-associated microRNAs in human skin.
- 2018
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
-
Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs are short non-coding RNAs that play key roles in regulating biological processes. In this study, we explored effects of chronological and photoageing on the miRNome of human skin. To this end, biopsies were collected from sun-exposed (outer arm, n = 45) and sun-protected (inner arm, n = 45) skin from fair-skinned (phototype II/III) healthy female volunteers of three age groups: young, 18-25 years, middle age, 40-50 years and aged, > 70 years. Strict inclusion criteria were used for photoageing scoring and for chronological ageing. Microarray analysis revealed that chronological ageing had minor effect on the human skin miRNome. In contrast, photoageing had a robust impact on miRNAs, and a set of miRNAs differentially expressed between sun-protected and sun-exposed skin of the young and aged groups was identified. Upregulation of miR-383, miR-145 and miR-34a and downregulation of miR-6879, miR-3648 and miR-663b were confirmed using qRT-PCR in sun-exposed skin compared with sun-protected skin. qRT-PCR analysis revealed that miR-383, miR-34a and miR-134 were differentially expressed in all three age groups both in chronological and photoageing, suggesting a synergetic effect of intrinsic and extrinsic ageing on their expression. In conclusion, our study identifies a unique miRNA signature which may contribute to skin ageing.
|
|
| 8. |
- Srivastava, Ankit, et al.
(författare)
-
MicroRNA-146a suppresses IL-17-mediated skin inflammation and is genetically associated with psoriasis.
- 2017
-
Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 139:2, s. 550-561
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Psoriasis is an immune-mediated inflammatory skin disease with a strong genetic background in which activation of IL-17 signaling is central in the pathogenesis. Little has been known about the role of noncoding RNAs, including microRNAs (miRNAs), in predisposition to the disease.OBJECTIVE: We sought to investigate the genetic association of single nucleotide polymorphisms in microRNA-146a (miR-146a) to psoriasis and to explore its function in the initiation and resolution of the disease.METHODS: mice in conjunction with the imiquimod-induced mouse model of psoriasis. The severity of psoriasis-like skin inflammation was evaluated at morphologic, histologic, and molecular levels. miR-146a was ectopically overexpressed and inhibited in keratinocytes treated with IL-17. Synthetic miR-146a was injected intradermally into mice.RESULTS: Here we report protective association of a functional polymorphism in the miR-146a precursor (rs2910164). Genetic deficiency in miR-146a leads to earlier onset and exacerbated pathology of skin inflammation, with increased expression of IL-17-induced keratinocyte-derived inflammatory mediators, epidermal hyperproliferation, and increased neutrophil infiltration. Moreover, miR-146a-deficient mice do not resolve inflammation after discontinuation of imiquimod challenge. The overexpression of miR-146a suppressed, whereas its inhibition enhanced, IL-17-driven inflammation in keratinocytes. Functionally, miR-146a impairs the neutrophil chemoattractant capacity of keratinocytes. Finally, delivery of miR-146a mimics into the skin leads to amelioration of psoriasiform skin inflammation, decreased epidermal proliferation, and neutrophil infiltration.CONCLUSIONS: Our results define a crucial role for miR-146a in modulating IL-17-driven inflammation in the skin.
|
|
| 9. |
|
|
| 10. |
- Srivastava, Ankit, et al.
(författare)
-
Tofacitinib Represses the Janus Kinase-Signal Transducer and Activators of Transcription Signalling Pathway in Keratinocytes.
- 2018
-
Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 0001-5555 .- 1651-2057. ; 98:8, s. 772-775
-
Tidskriftsartikel (refereegranskat)abstract
- Tofacitinib is a Janus kinase (JAK) inhibitor, which has shown efficacy in treating psoriasis. The mode of action of tofacitinib is not completely understood but it has been thought to be mediated by the inhibition of CD4+ T-cell activation. Here, we investigated whether the molecular targets of tofacitinib are expressed in keratinocytes, and whether tofacitinib can modulate the activity of the JAK/Signal Transducer and Activators of Transcription (STAT)-pathway in keratinocytes. Transcriptomic profiling of human keratinocytes treated with IL-22 in combination with tofacitinib revealed that tofacitinib could prevent the majority of IL-22-mediated gene expression changes. Pathway analysis of tofacitinib-regulated genes in keratinocytes revealed enrichment of genes involved in the JAK/STAT signalling pathway. Quantitative real-time-PCR confirmed the upregulation of S100A7 and downregulation of EGR1 expression by IL-22, which was prevented by tofacitinib pre-treatment. These results indicate a direct effect of tofacinitib on keratinocytes, which can have relevance for systemic as well as for topical treatment of psoriasis with tofacitinib.
|
|
| 11. |
- Xia, Ping, et al.
(författare)
-
miR ‐378a regulates keratinocyte responsiveness to interleukin‐17A in psoriasis
- 2022
-
Ingår i: British Journal of Dermatology. - : John Wiley & Sons. - 0007-0963 .- 1365-2133. ; 187:2, s. 211-222
-
Tidskriftsartikel (refereegranskat)abstract
- Background Psoriasis is an immune-mediated inflammatory skin disease, in which an interplay between infiltrating immune cells and keratinocytes sustains chronic skin inflammation. Interleukin (IL)-17A is a key inflammatory cytokine in psoriasis and its main cellular targets are keratinocytes.Objectives To explore the role of miR-378a in psoriasis.Methods Keratinocytes obtained from psoriatic skin and healthy epidermis were separated by magnetic sorting, and the expression of miR-378a was analysed by quantitative polymerase chain reaction. The regulation and function of miR-378a was studied using primary human keratinocytes. The expression of miR-378a was modulated by synthetic mimics, and nuclear factor kappa B (NF-κB) activity and transcriptomic changes were studied. Synthetic miR-378a was delivered to mouse skin in conjunction with induction of psoriasiform skin inflammation by imiquimod.Results We show that miR-378a is induced by IL-17A in keratinocytes through NF-κB, C/EBP-β and IκBζ and that it is overexpressed in psoriatic epidermis. In cultured keratinocytes, ectopic expression of miR-378a resulted in the nuclear translocation of p65 and enhanced NF-κB-driven promoter activity even in the absence of inflammatory stimuli. Moreover, miR-378a potentiated the effect of IL-17A on NF-κB nuclear translocation and downstream activation of the NF-κB pathway. Finally, injection of miR-378a into mouse skin augmented psoriasis-like skin inflammation with increased epidermal proliferation and induction of inflammatory mediators. Mechanistically, miR-378a acts as a suppressor of NFKBIA/IκBζ, an important negative regulator of the NF-κB pathway in keratinocytes.Conclusions Collectively, our findings identify miR-378a as an amplifier of IL-17A-induced NF-κB signalling in keratinocytes and suggest that increased miR-378a levels contribute to the amplification of IL-17A-driven skin inflammation in psoriasis.
|
|
