Interleukin 17 Receptor C, but not Polo-like Kinase 4, Plays a Critical Role in the Development of Skin Papilloma and Psoriasis in Mouse Models

Abstract

Abstract Introduction/Objective Hyperproliferation of epidermis is a histopathological hallmark of skin cancers and psoriasis. As a master regulator of centriole replication, overexpression of Polo-like kinase 4 (PLK4) has been identified in skin cancers. The aberrant proliferation of epidermal keratinocytes provoked by interleukin 17 (IL17) leads to psoriasis. Thus, targeting centriole replication and IL17 signaling simultaneously has been speculated as a potential therapeutic strategy. We hypothesized that inhibition of centriole duplication enhances the blockade of epidermal proliferation through Il17rc knockout. Methods/Case Report To test our hypothesis, 37 mice were used to imbed a two-stage model of skin carcinogenesis using wild-type (WT), IL17 receptor A (T779A) knock-in (Il17ra(T779A)-KI), and IL17 receptor C knock-out (Il17rc-KO) C57BL/6J mouse strains. Furthermore, an imiquimod-induced psoriasis model was established using 69 mice with the same strains. Results (if a Case Study enter NA) In our two-stage skin carcinogenesis model, Il17ra(T779A)-KI mice showed significantly decreased tumor incidence, tumor multiplicity, and tumor volume compared to the WT mice. Il-17rc-KO mice didn’t develop any skin papilloma. The skin papilloma formed never progressed into squamous carcinoma. However, centrinone, a selective inhibitor of PLK4, didn’t affect skin papilloma formation or epidermal thickening. In our psoriasis model, the epidermis thickness of Il-17rc-KO mice was dramatically decreased compared to WT and Il17ra(T779A)-KI mice. There was no significant difference between WT and Il17ra(T779A)-KI mice in terms of skin lesion and thickening of the epidermis. Centrinone didn’t stall the thickening of the epidermis in the psoriasis model. IHC staining showed significantly increased Ki67+ basal keratinocytes in the untreated skin of Il17ra(T779A)-KI male mice compared to WT mice. In imiquimod-treated skin, the percentage of Ki67+ basal keratinocytes significantly decreased in the order from WT, Il17ra(T779A)-KI to Il17rc-KO mice. Conclusion Our data suggest that the proliferation of keratinocytes is not stalled by centrinone but is inhibited by Il17rc-KO. Il17ra(T779A)-KI significantly inhibits skin papilloma formation, but slightly decreases epidermal thickening in the psoriasis model. However, Il17ra(T779A)-KI increases keratinocyte proliferation based on Ki67 staining in the untreated normal skin.