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Decreased Imiquimod-Induced Psoriasis-Like Skin Inflammation in a Novel MvdF250S/+ Knock-In Mouse Model

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Abstract

The mevalonate-diphosphate decarboxylase (MVD) gene, a member of the mevalonate pathway, plays a critical role in regulating the biosynthesis of cholesterol, steroid hormones, and non-steroid isoprenoids. Previous studies have suggested that the MVD c.746 T > C mutation is a major pathogenic gene of porokeratosis (PK), an autoinflammatory keratinization disease (AIKD) with unclear pathogenesis, few effective treatments, and no suitable animal model. To investigate the function of MvdF250S/+ mutation, we developed a novel MvdF250S/+ mouse model carrying an equivalent point mutation to the most common genetic variation among Chinese PK patients (MVDF249S/+) using CRISPR/Cas9 technology, which exhibited reduced cutaneous expression of Mvd protein. In the absence of external stimulation, MvdF250S/+ mice did not display specific phenotypes. However, upon induction with imiquimod (IMQ), MvdF250S/+ mice exhibited decreased susceptibility to skin acute inflammation compared to wild-type (WT) mice, as evidenced by reduced cutaneous proliferation and lower protein levels of IL-17a and IL-1β. Additionally, after IMQ induction, the MvdF250S/+mice exhibited downregulated collagen generation and upregulated expression of Fabp3 compared to WT mice, whereas no significant changes in the key genes related to cholesterol regulation were found. Furthermore, the MvdF250S/+ mutation activated autophagy. Our findings provided insights into the biological function of MVD in the skin.

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Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

MVD:

Mevalonate diphosphate decarboxylase

PK:

Porokeratosis

AIKD:

Autoinflammatory keratinization disease

IMQ:

Imiquimod

WT:

Wild type

sgRNA:

Single-guide RNA

PASI:

Psoriasis area and severity index

DEGs:

Differentially expressed genes

ECM:

Extracellular matrix

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Acknowledgements

We are grateful to Prof. Zhenghua Zhang as the leader of our team. Besides, we are grateful to Prof. Daqiang Li (Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University) and his lab for providing the experimental platform and guidance. And we thank Shanghai Model Organisms Center, Inc., and Genesky Biotechnologies Inc., (Shanghai, China) for their excellent technical support.

Funding

This work was supported by the National Natural Science Foundation of China (81974471).

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Author notes

  1. Yumeng La and Wenghong Wong contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai, People’s Republic of China

    Yumeng La, Wenghong Wong, Kexin Peng, Zhen Tian, Jiewen Pan, Jing Luan, Kexiang Yan, Qiaoan Zhang & Zhenghua Zhang

  2. Shanghai Model Organisms Center Inc, Shanghai, China

    Ruilin Sun

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Contributions

Zhenghua Zhang conceived this work and provided funding; Yumeng La performed experiments and wrote the original manuscript; Wenghong Wong also participated in experiments; Zhen Tian, Kexiang Yan, and Jing Luan provided technical assistance; Kexin Peng and Ruilin Sun performed statistical analysis; Qiaoan Zhang and Jiewen Pan performed pathology analysis. All authors read and approved the final manuscript.

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Correspondence to Zhenghua Zhang.

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La, Y., Wong, W., Peng, K. et al. Decreased Imiquimod-Induced Psoriasis-Like Skin Inflammation in a Novel MvdF250S/+ Knock-In Mouse Model. Inflammation 46, 1575–1586 (2023). https://doi.org/10.1007/s10753-023-01828-z

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