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Published on: August 6, 2020
The p300/CBP Inhibitor A485 Normalizes Psoriatic Fibroblast Gene Expression In Vitro and Reduces Psoriasis-Like Skin
Jihye Kim1, Yuliang He1, Sabrina Tormen1
1Institute of Pharmaceutical Sciences (IPW), Swiss Federal Institute of Technology (ETH Zurich), Zurich, Switzerland.
Abstract:
Psoriasis is a chronic inflammatory skin disease that often recurs at the same locations, indicating potential epigenetic changes in lesional skin cells. In this study, we discovered that fibroblasts isolated from psoriatic skin lesions retain an abnormal phenotype even after several passages in culture. Transcriptomic profiling revealed the upregulation of several genes, including the extra domain A splice variant of fibronectin and ITGA4 in psoriatic fibroblasts. A phenotypic library screening of small-molecule epigenetic modifier drugs revealed that selective CBP/p300 inhibitors were able to rescue the psoriatic fibroblast phenotype, reducing the expression levels of extra domain A splice variant of fibronectin and ITGA4. In the imiquimod-induced mouse model of psoriasis-like skin inflammation, systemic treatment with A485, a potent CBP/p300 blocker, significantly reduced skin inflammation, immune cell recruitment, and inflammatory cytokine production. Our findings indicate that epigenetic reprogramming might represent a new approach for the treatment and/or prevention of relapses of psoriasis.
Insights
Psoriasis fibroblasts show abnormal gene expression due to potential epigenetic changes. CBP/p300 inhibitors reversed these changes and reduced inflammation in a mouse model, suggesting epigenetic reprogramming as a psoriasis treatment.
Area of Science:
- Dermatology
- Epigenetics
- Molecular Biology
Background:
- Psoriasis is a chronic inflammatory skin condition characterized by recurring lesions.
- Recurrence suggests underlying epigenetic alterations in skin cells.
- Psoriatic fibroblasts exhibit persistent abnormal phenotypes in vitro.
Purpose of the Study:
- To investigate epigenetic dysregulation in psoriatic fibroblasts.
- To identify potential therapeutic targets for psoriasis treatment.
Main Methods:
- Fibroblast isolation and culture from psoriatic lesions.
- Transcriptomic profiling to identify gene expression changes.
- Phenotypic screening of small-molecule epigenetic modifiers.
- In vivo validation using an imiquimod-induced mouse model.
Main Results:
- Psoriatic fibroblasts overexpressed genes like fibronectin extra domain A and ITGA4.
- Selective CBP/p300 inhibitors normalized fibroblast phenotype and gene expression.
- Systemic administration of CBP/p300 inhibitor A485 reduced skin inflammation, immune cell infiltration, and cytokine production in mice.
Conclusions:
- Epigenetic reprogramming by targeting CBP/p300 is a promising therapeutic strategy for psoriasis.
- This approach may offer a new way to treat psoriasis and prevent lesion recurrence.
