Decreased Imiquimod-Induced Psoriasis-Like Skin Inflammation in a Novel Mvd F250S/+ Knock-In Mouse Model.

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 Mvd ^F250S/+ mutation, we developed a novel Mvd ^F250S/+ mouse model carrying an equivalent point mutation to the most common genetic variation among Chinese PK patients (MVD ^F249S/+ ) using CRISPR/Cas9 technology, which exhibited reduced cutaneous expression of Mvd protein. In the absence of external stimulation, Mvd ^F250S/+ mice did not display specific phenotypes. However, upon induction with imiquimod (IMQ), Mvd ^F250S/+ 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 Mvd ^F250S/+ 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 Mvd ^F250S/+ mutation activated autophagy. Our findings provided insights into the biological function of MVD in the skin.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)