MicroRNA let-7b inhibits keratinocyte differentiation by targeting IL-6 mediated ERK signaling in psoriasis

Yan Wu,Qingchun Diao,Liu Liu,Chunxiang Bian,Muhammad Farrukh Nisar,Xiangyu Hu,Jörg W Bartsch,Xuemei Jiang,Julia Li Zhong,Maojiao Zhong

doi:10.1186/s12964-018-0271-9

Abstract

BackgroundThe extensive involvement of microRNA (miRNA) in the pathophysiology of psoriasis is well documented. However, in order for this information to be useful in therapeutic manipulation of miRNA levels, it is essential that detailed functional mechanisms are elucidated. This study aimed to explore the effects of IL-6 targeting by let-7b and ERK1/2 mediated signaling on keratinocyte differentiation in psoriasis.MethodsFollowing imiquimod cream (IMQ) application to let-7bTG (keratinocyte-specific let-7b overexpression mouse) and control mice for 7 days, we analyzed erythema, scaling and thickening of skin. A dual luciferase reporter assay and bioinformatics was carried out to detect target gene of let-7b. Additionally, the differentiation markers were measured. Immunohistochemistry analyses demonstrate a relationship of let-7b with IL-6 and ERK signaling.Resultswe found let-7bTG inhibits acanthosis and reduces the disease severity by treatment with IMQ compared to wild-type mice. Further study illustrated that let-7b promotes differentiation of keratinocytes in vivo and in vitro. Using bioinformatics and reporter gene assays, we found that IL-6 is a target gene of let-7b. In psoriasis, high expression levels of IL-6 lead to increased acivation of p-ERK1/2. High levels of let-7bTG transgene expression suppresses IL-6 expression and leads to increased keratinocyte differentiation. Moreover, let-7b acts as an upstream negative regulator of the ERK signaling pathway in keratinocytes of psoriasis.ConclusionsOur result reveals a previously unknown mechanism for regulation of IL-6 levels during psoriasis by let-7b and highlights a critical role for the ERK1/2 signaling pathway in epidermal differentiation during psoriasis.Trial registrationThe ethical approval for this study was from the Affiliated Hospital of Medical University of Anhui _ Fast_ PJ2017–11–14.

Highlights

The extensive involvement of microRNA in the pathophysiology of psoriasis is well documented
Our study demonstrates that let-7b regulates keratinocyte differentiation through targeting Interleukin 6 (IL-6)-dependent ERK1/2 signaling that may play an important role in the pathogenesis of psoriasis
Compared with imiquimod cream (IMQ)-treated wild-type (WT) and to mice treated with an emollient cream as control, let-7bTG mice showed a striking decrease of skin inflammation as reflected by an increased modified Psoriasis Area and Severity Index which was adapted to mice pathology (Fig. 1c)

Summary

Introduction

The extensive involvement of microRNA (miRNA) in the pathophysiology of psoriasis is well documented. This study aimed to explore the effects of IL-6 targeting by let-7b and ERK1/2 mediated signaling on keratinocyte differentiation in psoriasis. A dual luciferase reporter assay and bioinformatics was carried out to detect target gene of let-7b. Results: we found let-7bTG inhibits acanthosis and reduces the disease severity by treatment with IMQ compared to wild-type mice. Further study illustrated that let-7b promotes differentiation of keratinocytes in vivo and in vitro. Using bioinformatics and reporter gene assays, we found that IL-6 is a target gene of let-7b. High expression levels of IL-6 lead to increased acivation of p-ERK1/2. High levels of let-7bTG transgene expression suppresses IL-6 expression and leads to increased keratinocyte differentiation. Let-7b acts as an upstream negative regulator of the ERK signaling pathway in keratinocytes of psoriasis. Psoriasis undergoes three different processes of cellular alteration in skin: abnormal

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