Downregulation of miR-145-5p contributes to hyperproliferation of keratinocytes and skin inflammation in psoriasis.
Br J Dermatol. 2018 Sep 30;:
Authors: Yan JJ, Qiao M, Li RH, Zhao XT, Wang XY, Sun Q
BACKGROUND: The extensive involvement of microRNAs (miRNAs) in the pathogenesis of psoriasis is well documented. However, little is known about the contribution of specific miRNAs to the prevalence of this disease.
OBJECTIVES: Our study aimed to explore the role of miR-145-5p in psoriasis.
METHODS: MiRNA microarray analysis was performed in 4 patients with psoriasis and 4 controls. qRT-PCR and fluorescence in situ hybridization (FISH) were used to identify the dysregulated miRNAs. Luciferase assays were performed to determine whether miR-145-5p targets Mixed-lineage kinase 3 (MLK3). Cell counting kit-8 (CCK-8) and Magnetic Luminex® assays were performed to measure cell proliferation and chemokine secretion. Westernblot analysis was used to investigate the protein levels of MLK3 and its downstream effectors. Mouse models of psoriasis were established for in vivo experiments.
RESULTS: MiR-145-5p was down-regulated in psoriasis lesional skin. Luciferase assays showed that MLK3 is a direct target of miR-145-5p. Overexpression of miR-145-5p in normal human epidermal keratinocytes (NHEKs) suppressed cell proliferation and secretion of chemokines. In contrast, silencing miR-145-5p promoted NHEK proliferation and increased chemokine secretion. Silencing MLK3 abrogated miR-145-5p inhibitor-induced promotion of cell proliferation and chemokine expression. MiR-145-5p regulates NF-ҡB and STAT3 by targeting MLK3. Delivery of agomiR-145-5p into the skin decreased epidermal hyperplasia and ameliorated psoriasis-like dermatitis. Delivery of antagomiR-145-5p led to the opposite effects.
CONCLUSIONS: Our findings indicate that miR-145-5p negatively regulates proliferation and chemokine secretion of NHEKs by targeting MLK3, and downregulation of miR-145-5p contributes to skin inflammation in psoriasis lesions. This article is protected by copyright. All rights reserved.
PMID: 30269330 [PubMed – as supplied by publisher]