Psoriasis is characterized by scaly erythematous plaques resulted from keratinocytes hyperproliferation, immune cells infiltration and angiogenesis . The pathophysiological process is orchestrated by many cytokines including IL-1β, IL-6, TNF-α, IL-23, IL-17A, IL-22 and so on , , of which, IL-17A is the key player . During psoriasis development, IL-17 stimulates CCL20 expression by keratinocytes to attract CCR6+ IL-17A+cells including Th17, ILC3, Tc17, and γδ T cells into the skin to amplify the inflammation . The remarkable therapeutic efficacy of anti-IL-17A biologics further confirm the fundamental role of IL-17A in psoriasis pathogenesis , .
Although the biologics opens a new era of psoriasis therapy, maximumly less than 20–40% of patients achieved complete response (PASI100) to the initial anti-IL-17A biologics treatment, given that some of them experience mild to moderate relapse later on . The majority of patients only achieved partial response (PASI 50 or 75) with residual lesions left particularly on elbows and pretibial skin . Thus, the combination therapy with topical medicine is an optional strategy as considering the overall safety and efficacy . However, topical medicines are only limited to several categories such topical corticosteroids, calcineurin inhibitors, vitamin D derivatives and narrow-band UVB. It is very often that the residual lesions failed to response to all available topical medicine. Therefore, topical medications targeting new signaling pathway is even more in urgent need in the biologics era to meet the patients’ requirement of complete clearance of skin lesions.
Histone deacetylases (HDACs) are enzymes that remove acetyl from lysine residues on histones and non-histone proteins and result in chromatin condensation and transcription repression . HDAC1 belongs to the class I HDAC family. Previous research observed that HDAC1 was overexpressed in psoriatic skin and peripheral blood mononuclear cells (PBMCs), implying a possible role of HDAC1 in psoriasis pathogenesis , . Entinostat is a selective inhibitors of histone deacetylases (HDAC) 1 and 2. Systemic administration of Entinostat has been widely explored in clinic trials to treat various solid tumors and hematological malignancies, . Its anti-tumor activity attributes to the direct effects on tissue-specific tumor cells, innate and adaptive immune cells as well. Therefore, we investigated the topical therapeutic potentials of Entinostat on psoriasis in this study.
Bioinformatics analysis of RNA-sequencing data
Gene Expression Omnibus (GEO) is a public gene expression database containing a large amount of high-throughput sequencing submitted by research institutes worldwide . The dataset GSE121212 used in this work was downloaded from GEO, which contains skin transcriptomes of lesions from 28 psoriasis vulgaris (PV) and normal skin from 38 healthy control (NC). We defined the IL17A-correlated expression network as described by Shao, S. et al.. Briefly, The mapped counts of dataset GSE121212
The overexpression of HDAC1 in psoriatic lesions
We first investigate the potential link between psoriasis and HDAC1. The dataset GSE121212 was downloaded from GEO and converted into a log2-based expression intensity using the voom transformation. It contains lesional skin transcriptomes from 28 psoriasis patients and normal skin transcriptomes from 38 healthy individuals. Overall, the expression of 13315 gene was positively correlated with IL-17A (rs>0). The correlation coefficient varied among these 13315 genes. To determine an appropriate
In the present study, we demonstrate that topical Entinostat, a HDAC1 inhibitor is a potential topical therapeutic agent for psoriasis. It improves imiquimod-induced psoriasiform dermatitis with less IL-17A+ γδ T cells infiltration and great reduction of psoriasis-related cytokines in skin. In the context of psoriasis, Entinostat not only suppresses γδ+IL-17A T cells generation and IL-17-related cytokines production by T cells, but disrupts the cross talk between keratinocytes and T cells with
This study was supported by the National Natural Science Foundation of China (grants 81872524, 82073431) and China Postdoctoral Science Foundation [grant 2022M723613].
CRediT authorship contribution statement
Yanyun Jiang: Conceptualization, Methodology, Validation, Data curation, Writing – original draft, Project administration. Siyao Lu: Methodology, Investigation. Yuxian Lai: Methodology. Liangchun Wang: Conceptualization, Writing – review & editing, Supervision, Funding acquisition.
Conflict of interest
All authors have no conflicts of interest to declare.
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© 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.