Psoriatic skin inflammation is promoted by c‐Jun/AP‐1‐dependent CCL2 and IL‐23 expression in dendritic cells

Novoszel, Philipp; Holcmann, Martin; Stulnig, Gabriel; Fernandes, Cristiano De Sa; Zyulina, Victoria; Borek, Izabela; Linder, Markus; Bogusch, Alexandra; Drobits, Barbara; Bauer, Thomas; Tam‐Amersdorfer, Carmen; Brunner, Patrick M.; Stary, Georg; Bakiri, Latifa; Wagner, Erwin F.; Strobl, Herbert; Sibilia, Maria

doi:10.15252/emmm.202012409

Cited by 55 publications

(39 citation statements)

References 63 publications

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“…The NK cells with high expression of NKG2C killed autoreactive T cells and respond to virus-infected cells, which might have an impact on psoriasis prevention (Patel et al, 2013). The inactivation and activation of DCs was an important mechanism to maintain a moderate immune response, which not only played a role in maintaining psoriasis inflammation but also participated in the initiation of inflammation (Wang and Bai, 2020;Novoszel et al, 2021). The neutrophils/lymphocyte ratio and neutrophils activity were significantly increased in patients with psoriasis compared with healthy controls (Wang and Jin, 2020).…”

Section: Discussionmentioning

confidence: 99%

Identification of Potential Biomarkers for Psoriasis by DNA Methylation and Gene Expression Datasets

et al. 2021

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DNA methylation (DNAm) plays an important role in the pathogenesis of psoriasis through regulating mRNA expressions. This study aimed to identify hub genes regulated by DNAm as biomarkers of psoriasis. Psoriatic skin tissues gene expression and methylation datasets were downloaded from Gene Expression Omnibus (GEO) database. Subsequently, multiple computational approaches, including immune infiltration analysis, enrichment analysis, protein–protein interaction (PPI) network establishment, and machine learning algorithm analysis (lasso, random forest, and SVM-RFE), were performed to analyze the regulatory networks, to recognize hub genes, and to clarify the pathogenesis of psoriasis. Finally, the hypermethylated genes were used to immune cell infiltration analysis, which revealed that psoriasis skin tissues were mainly composed of activated dendritic cells, resting mast cells, T follicular helper cells (cTfh), etc. Differentially expressed-methylated genes (DEMGs) were identified and partitioned into four subgroups and the 97 significantly hypermethylated and downregulated (hyper-down) genes accounted for the highest proportion (47%). Hyper-down genes were mainly enriched in glucose homeostasis, AMP-activated protein kinase (AMPK) signaling pathway, lipid storage disease, partial lipodystrophy, and insulin resistance. Furthermore, insulin receptor substrate 1 (IRS1), Rho guanine nucleotide exchange factor 10 (ARHGEF10) and retinoic acid induced 14 (RAI14) were identified as potential targets. These findings provided new ideas for future studies of psoriasis on the occurrence and the molecular mechanisms.

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Section: Discussionmentioning

confidence: 99%

Identification of Potential Biomarkers for Psoriasis by DNA Methylation and Gene Expression Datasets

et al. 2021

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“…The antibiotic azithromycin can improve the severity of IMQ-induced mouse psoriasis by interfering with the lysosomal processing of TLR7 maturation and signaling in DC [ 145 ]. Blockage of JNK/c-Jun signaling, which is required for the TLR7-IMQ mediated inflammation but not for normal DC skin development, was found to reduce the DC IL-23 production and relieve the psoriasis-like skin inflammation [ 146 ].…”

Section: Dcs In Chronic Inflammation Of Psoriasismentioning

confidence: 99%

Dendritic Cells and CCR7 Expression: An Important Factor for Autoimmune Diseases, Chronic Inflammation, and Cancer

Brandum

Jørgensen

Hjortø

2021

IJMS

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Chemotactic cytokines—chemokines—control immune cell migration in the process of initiation and resolution of inflammatory conditions as part of the body’s defense system. Many chemokines also participate in pathological processes leading up to and exacerbating the inflammatory state characterizing chronic inflammatory diseases. In this review, we discuss the role of dendritic cells (DCs) and the central chemokine receptor CCR7 in the initiation and sustainment of selected chronic inflammatory diseases: multiple sclerosis (MS), rheumatoid arthritis (RA), and psoriasis. We revisit the binary role that CCR7 plays in combatting and progressing cancer, and we discuss how CCR7 and DCs can be harnessed for the treatment of cancer. To provide the necessary background, we review the differential roles of the natural ligands of CCR7, CCL19, and CCL21 and how they direct the mobilization of activated DCs to lymphoid organs and control the formation of associated lymphoid tissues (ALTs). We provide an overview of DC subsets and, briefly, elaborate on the different T-cell effector types generated upon DC–T cell priming. In the conclusion, we promote CCR7 as a possible target of future drugs with an antagonistic effect to reduce inflammation in chronic inflammatory diseases and an agonistic effect for boosting the reactivation of the immune system against cancer in cell-based and/or immune checkpoint inhibitor (ICI)-based anti-cancer therapy.

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“…EGFR ∆ep and c-Jun ∆ep mice were generated as previously described [3,9]. All mice in this study are in the C57BL/6 background and were bred and maintained in the facilities of the Medical University of Vienna in accordance with institutional policies and federal guidelines.…”

Section: Micementioning

confidence: 99%

“…Therefore, our data indicate that the dominant driver of TSLP expression during skin barrier defects in explant cultures is the JNK-AP1 axis. The JNK signalling pathway is responsible for AP-1 transcriptional activation [9]. We next tested if we could influence skin barrier immunity and TSLP expression via the inhibition of the upstream JNK pathway in ex-vivo mouse skin explants.…”

Section: Jnk Pathway Inhibitor Blocks Tslp Expression Ex Vivomentioning

confidence: 99%

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Ex-Vivo Skin Explant Culture Is a Model for TSLP-Mediated Skin Barrier Immunity

Bauer

Gubi

Klufa

et al. 2021

Life

Self Cite

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The skin is the outermost barrier protecting the body from pathogenic invasion and environmental insults. Its breakdown initiates the start of skin inflammation. The epidermal growth factor (EGFR) on keratinocytes protects this barrier, and its dysfunction leads to atopic dermatitis-like skin disease. One of the initial cytokines expressed upon skin barrier breach and during atopic dermatitis is TSLP. Here, we describe the expression and secretion of TSLP during EGFR inhibition and present an ex-vivo model, which mimics the early events after barrier insult. Skin explants floated on culture medium at 32 °C released TSLP in parallel to the activation of the resident Langerhans cell network. We could further show the up-regulation and activation of the AP-1 family of transcription factors during atopic-like skin inflammation and its involvement in TSLP production from the skin explant cultures. Inhibition of the c-Jun N-terminal kinase pathway led to a dose-dependent blunting of TSLP release. These data indicate the involvement of AP-1 during the early stages of atopic-like skin inflammation and highlight a novel therapeutic approach by targeting it. Therefore, skin explant cultures mimic the early events during skin barrier immunity and provide a suitable model to test therapeutic intervention.

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Psoriatic skin inflammation is promoted by c‐Jun/AP‐1‐dependent CCL2 and IL‐23 expression in dendritic cells

Cited by 55 publications

References 63 publications

Identification of Potential Biomarkers for Psoriasis by DNA Methylation and Gene Expression Datasets

Identification of Potential Biomarkers for Psoriasis by DNA Methylation and Gene Expression Datasets

Dendritic Cells and CCR7 Expression: An Important Factor for Autoimmune Diseases, Chronic Inflammation, and Cancer

Ex-Vivo Skin Explant Culture Is a Model for TSLP-Mediated Skin Barrier Immunity

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