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

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

PROVIDER: PRJNA603350 | ENA |

REPOSITORIES: ENA

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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: Not available

| S-EPMC7260032 | biostudies-literature

Influence of rYopM treatment on IMQ-induced psoriasiform dermatitis

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

| PRJNA486825 | ENA

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

Immunity to commensal skin fungi promotes psoriasiform skin inflammation

Project description:Immunity to commensal skin fungi promotes psoriasiform skin inflammation

| PRJNA605153 | ENA

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

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

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

| PRJNA510398 | ENA

Skin Microbiome in Atopic Dermatitis

Project description:Skin Microbiome in Atopic Dermatitis

| PRJEB21789 | ENA

Synthesis and activity of the salicylic acid ester of bakuchiol in psoriasiform keratinocytes and skin substitutes

Project description:Background: Topical retinoids are effective in retarding skin aging and restoring homeostasis in skin conditions, such as psoriasis. However their adverse effects, which include irritation (retinoid dermatitis), photosensitivity and teratogenicity, limit their use level and patient compliance. Development of a retinoid analogue with minimal adverse effects would allow a broader and more compliant use. Objective: Here we report the synthesis of a novel molecule - bakuchiol salicylate (bakusylan) with the gene expression modulatory profile similar to retinoids, using as reference 3 prescription retinoids - tretinoin, tazarotene and adapalene. Methods: Having a structure entirely different from existing retinoids, we hypothesized that at least a partial uncoupling of retinoid adverse effects from retinoid skin normalizing activity may be obtained with bakuchiol salicylate. This hypothesis was tested in psoriasiform cultures of keratinocytes and organotypic skin substitutes by DNA microarrays and custom PCR arrays. Results: The evaluation of the bioactivity of bakuchiol salicylate revealed the elimination of several components of the retinoid-like proinflammatory response and teratogenic signature without a substantial loss of normalizing potential. A possible mechanism of action consisting in keratinocyte desensitization to cytokine signaling through the inhibition of the STAT1/3/interferon inflammatory signal transduction axis has also been identified. Conclusion: Bipartite materials obtained by merging two skin-active entities with specific, complementary bioactivities, such as bakuchiol and salicylic acid, may deliver a new class of functional retinoids.

2017-03-24 | GSE79642 | GEO

Transcription data from Normal Skin and Nonlesional and Lesional Atopic Dermatitis/Eczema Skin

Project description:Atopic dermatitis (AD) is a common pruritic dermatitis with macroscopically nonlesional skin that is often abnormal. Therefore, we used high-density oligonucleotide arrays to identify cutaneous gene transcription changes associated with early AD inflammation as potential disease control targets. Skin biopsy specimens analyzed included normal skin from five healthy nonatopic adults and both minimally lesional skin and nearby or contralateral nonlesional skin from six adult AD patients. Keywords: disease state analysis

2006-10-01 | GSE5667 | GEO

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