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Mechanistic and pharmacological assessment of murine IL-23 mediated psoriasiform dermatitis; implications for drug discovery

ABSTRACT: Mechanistic and pharmacological assessment of murine IL-23 mediated psoriasiform dermatitis; implications for drug discovery

PROVIDER: PRJNA510398 | ENA |

REPOSITORIES: ENA

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Mechanistic and pharmacological assessment of murine IL-23 mediated psoriasiform dermatitis; implications for drug discovery

Project description:The goal of our study is to is to provide a comprehensive disease and pharmacological assessment of IL-23 driven skin inflammation and its similarity to human psoriatic skin.

2018-12-18 | GSE123971 | GEO

Influence of rYopM treatment on IMQ-induced psoriasiform dermatitis

Project description:Influence of rYopM treatment on IMQ-induced psoriasiform dermatitis

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KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease

Project description:Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease hypothesized to promote inflammation via cleavage of protease-activated receptors (PAR)1 and PAR2. KLK6 levels are elevated in multiple inflammatory and autoimmune conditions, but no definitive role in pathogenesis has been established. Here, we show that skin-targeted overexpression of KLK6 causes generalized, severe psoriasiform dermatitis with spontaneous development of debilitating psoriatic arthritis-like joint disease. The psoriatic skin and joint phenotypes are reversed by normalization of skin KLK6 levels and attenuated following genetic elimination of PAR1 but not PAR2. Conservation of this regulatory pathway was confirmed in human psoriasis using vorapaxar, an FDA-approved PAR1 antagonist, on explanted lesional skin from psoriasis patients. Beyond defining a critical role for KLK6-PAR1 signaling in promoting psoriasis, our results demonstrate that KLK6-PAR1-mediated inflammation in the skin alone is sufficient to drive inflammatory joint disease. Further, we identify PAR1 as a promising cytokine-independent target in therapy of psoriasis and psoriatic arthritis.

2020-03-25 | GSE144312 | GEO

KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease

Project description:KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease

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FAM3C/ILEI protein is elevated in psoriatic lesions and triggers psoriasiform hyperproliferation in mice

Project description:Inducible keratinocyte-specific ILEI overexpression in mice (K5-ILEIind) recapitulates many aspects of psoriasis following TPA challenge, primarily manifested by impaired epidermal differentiation and increased neutrophil recruitment. Mechanistically, ILEI triggers Erk and Akt signaling, which then activate STAT3 via Ser727 phosphorylation. Keratinocyte-specific ILEI deletion ameliorates TPA-induced skin inflammation. A transcriptomic ILEI signature obtained from the K5-ILEIind model shows enrichment in several signaling pathways also found in psoriasis and identifies urokinase as a targetable enzyme to counteract ILEI activity. Pharmacological inhibition of urokinase in TPA-induced K5-ILEIind mice results in significant improvement of psoriasiform symptoms by reducing ILEI secretion. The ILEI signature distinguishes psoriasis from healthy skin with uPA ranking among the top “separator” genes. Our study identifies ILEI as a key driver in psoriasis, indicates the relevance of ILEI-regulated genes for disease manifestation and shows the clinical impact of ILEI and urokinase as novel potential therapeutic targets in psoriasis.

2023-04-12 | E-MTAB-12849 | biostudies-arrayexpress

RNA-Seq atopic dermatitis transcriptome profiling provides insights into novel disease mechanisms with potential therapeutic implications

Project description:Purpose: provide evidence that RNA-seq can add information to transcriptome profiling already discovered by other technologies for atopic dermatitis Methods: mRNA profiles of 20 atopic dermatitis were analyzed to compare lesional and non-lesional skin, then transcriptomes found by reads were compared to Microarray and RT-PCR Results:RNA-seq provided complementary genes to AD transcriptome IL-36 and TREM-1 Conclusions: Our study represents the first analysis of lesional AD tissue by RNA-seq and comparison to microarray and RT-PCR

2015-09-29 | GSE65832 | GEO

Soluble adenylyl cyclase induces type 17 inflammation and is a potential therapeutic target in psoriasis

Project description:Cyclic AMP (cAMP) has a key role in psoriasis pathogenesis, as indicated by the therapeutic efficacy of phosphodiesterase inhibitors that prevent the degradation of cAMP. However, whether soluble adenylate cyclase (sAC) (encoded by the ADCY10 gene), which is an important source for cAMP, is involved in Th17 cell-mediated inflammation or could be an alternative therapeutic target in psoriasis is unknown. We have utilized the imiquimod model of murine psoriasiform dermatitis to address this question. Adcy10-/- mice had reduced erythema, scaling and swelling in the skin and Th17 cell numbers in the draining lymph nodes, compared with wild-type mice after induction of psoriasiform dermatitis with imiquimod. During Th17 polarization in vitro, naïve T cells from Adcy10-/- mice were unable to differentiate to Th17 cells and RNA-seq analysis revealed that sAC was also essential for Th17 cell activation. Interestingly, sAC did not impact Th17 lineage-defining transcription factors (such as RORc and cMAF) but rather was required for CREB-dependent gene expression. Finally, topical application of small molecule sAC inhibitors (sACi) reduced imiquimod-induced psoriasiform dermatitis and IL17 gene expression in the skin. Collectively, these findings demonstrate that sAC is a key factor for inducing type 17 inflammation in the skin and sACi could provide an alternative class of topical therapeutics for psoriasis.

2021-10-01 | GSE175470 | GEO

Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk.

Project description: Not available

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Genome-Wide Profiling of Lesional and Non-Lesional Skin from Atopic Dermatitis, Psoriasis, and Contact Dermatitis Skin

Project description:Genome-Wide Profiling of Lesional and Non-Lesional Skin from Atopic Dermatitis, Psoriasis, and Contact Dermatitis Skin

2020-06-23 | GSE153007 | GEO

mRNA expression of Atopic Dermatitis keratinocytes

Project description:mRNA array analysis of total RNA from primary kertinocytes from three healthy controls, three atopic dermatitis patients and three psoriasis patients was carried out

2012-06-01 | E-MTAB-728 | biostudies-arrayexpress

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