Highlights
- •MCM6 is upregulated in psoriatic lesions and required for keratinocytes proliferation.
- •MCM6 is regulated by the JAK/STAT3 pathway in keratinocytes.
- •Benvitimod could inhibit the JAK/STAT3 pathway by activating AHR of keratinocytes.
Abstract
Background
Benvitimod (Tapinarof), as a small-molecule topical therapeutical aryl hydrocarbon
receptor (AHR)-modulating agent, is in clinical development for treating psoriasis
and atopic dermatitis. Benvitimod reduces proinflammatory cytokines in psoriasis by
specifically binding and activation of AHR. However, whether benvitimod can inhibit
keratinocyte proliferation remains unclear. Minichromosome maintenance protein 6 (MCM6)
is a key element of the prereplication complex (pre-RC) assembly which is one of the
essential steps in the initiation of DNA replication for cell proliferation.
Objectives
This study aimed to determine whether benvitimod could reduce the excessive proliferation
of psoriatic keratinocytes by inhibiting MCM6.
Methods
We examined the inhibitory effect of benvitimod on MCM6-mediated proliferation of
keratinocytes by HaCaT cells in vitro and an IMQ-induced psoriatic model of mice in vivo.
Results
Epidermal MCM6 expression was enhanced in the skin lesions of psoriatic patients.
The experiments further revealed that MCM6 was required for the proliferation of keratinocytes
and governed by the IL-22/STAT3 pathway. In addition, the antiproliferation effect
of benvitimod is achieved by the inhibition of p-JAK1 and p-JAK2, which further restrained
the activation of STAT3 in keratinocytes. Lastly, benvitimod could repressed imiquimod-induced
skin lesions and the expression of epidermal MCM6 and p-STAT3 in mice. Moreover, knockdown
of AHR in keratinocytes enhanced the activation of JAK1 and JAK2.
Conclusion
The findings reveal that benvitimod could decrease MCM6-mediated proliferation of
keratinocytes by affecting the JAK/STAT3 pathway, thereby serving as a new treatment
modality for psoriasis.
Keywords
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Article info
Publication history
Published online: January 29, 2023
Accepted:
January 27,
2023
Received in revised form:
January 17,
2023
Received:
October 7,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
