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Downregulation of miR‐145‐5p contributes to hyperproliferation of keratinocytes and skin inflammation in psoriasis
Author(s) -
Yan J.J.,
Qiao M.,
Li R.H.,
Zhao X.T.,
Wang X.Y.,
Sun Q.
Publication year - 2019
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.17256
Subject(s) - downregulation and upregulation , psoriasis , inflammation , cancer research , keratinocyte , chemistry , medicine , microbiology and biotechnology , immunology , biology , biochemistry , gene , in vitro
Summary Background The extensive involvement of micro RNA s (mi RNA s) in the pathogenesis of psoriasis is well documented. However, little is known about the contribution of specific mi RNA s to the prevalence of this disease. Objectives To explore the role of miR‐145‐5p in psoriasis. Methods mi RNA microarray analysis was performed in four patients with psoriasis and four controls. Quantitative reverse‐transcriptase polymerase chain reaction and fluorescence in situ hybridization were used to identify the dysregulated mi RNA s. Luciferase assays were performed to determine whether miR‐145‐5p targets mixed‐lineage kinase ( MLK )3. CCK ‐8 assay and Magnetic Luminex Assay were performed to measure cell proliferation and chemokine secretion. Western blot analysis was used to investigate the protein levels of MLK 3 and its downstream effectors. Mouse models of psoriasis were established for in vivo experiments. Results miR‐145‐5p was downregulated in psoriatic lesional skin. Luciferase assays showed that MLK 3 is a direct target of miR‐145‐5p. Overexpression of miR‐145‐5p in normal human epidermal keratinocytes ( NHEK s) suppressed cell proliferation and secretion of chemokines. In contrast, silencing miR‐145‐5p promoted NHEK proliferation and increased chemokine secretion. Silencing MLK 3 abrogated miR‐145‐5p inhibitor‐induced promotion of cell proliferation and chemokine expression. miR‐145‐5p regulates nuclear factor‐κB and signal transducer and activator of transcription 3 by targeting MLK 3. 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 NHEK s by targeting MLK 3, and downregulation of miR‐145‐5p contributes to skin inflammation in psoriasis lesions.