Abstract
Psoriasis is an auto-inflammatory skin disease characterized by abnormal activation of epidermal keratinocytes, aberrant neovascularization, and dysregulation of immune cells. MicroRNAs are small non-coding RNAs that mainly function in the post-transcriptional regulation of gene expression. Recently, accumulating evidence has demonstrated that expression of microRNAs is dysregulated in psoriasis patients and microRNAs play key roles in psoriasis pathogenesis. Downregulation of miR-193b-3p has been identified to be associated with psoriasis development. However, the precise functions and action mechanisms of miR-193b-3p in psoriasis pathogenesis remain unclear. In this study, we confirmed the downregulation of miR-193b-3p in psoriasis patients, psoriasis-like inflammatory cellular models, and an imiquimod (IMQ) -induced mouse model. A negative correlation was found between miR-193b-3p level and patient Psoriasis Area and Severity Index (PASI) score. Furthermore, miR-193b-3p suppressed proliferation, inflammatory-factor secretion, and the STAT3 and NF-κB signaling pathways in keratinocytes. Importantly, intradermal injection of agomiR-193b-3p blocked, whereas antagomiR-193b-3p augmented, the psoriasis-like inflammation in the IMQ-induced mouse model. Bioinformatics analysis and the dual-luciferase reporter assay showed that miR-193b-3p targets ERBB4 3ʹ untranslated region (UTR). In addition, ERBB4 induced proliferation, inflammatory-factor production, and the STAT3 and NF-κB pathways in keratinocytes. Most importantly, forced expression of ERBB4 could attenuate the effects of miR-193b-3p in keratinocytes, indicating that miR-193b-3p inhibits keratinocyte activation by directly targeting ERBB4. In conclusion, our findings demonstrated that the miR-193b-3p–ERBB4 axis underlies the hyperproliferation and aberrant inflammatory-factor secretion of psoriatic keratinocytes, providing a novel, microRNA-related causal mechanism and a potential therapeutic target in psoriasis.
Highlights
Psoriasis is a chronic and inflammatory dermatosis that affects approximately 3% of the world population, which seriously impairs the life quality of psoriasis patients [1, 2]
Psoriasis is characterized by abnormal proliferation and/or differentiation of keratinocytes, neovascularization, and infiltration of neutrophils, major lymphocytes including T cells, and dendritic cells into epidermis and dermis [1, 2]
It is widely accepted that dysregulation of the crosstalk between epidermal keratinocytes and immune cells plays a critical role in the psoriatic epidermal hyperplasia [3, 4]
Summary
Psoriasis is a chronic and inflammatory dermatosis that affects approximately 3% of the world population, which seriously impairs the life quality of psoriasis patients [1, 2]. MicroRNAs are endogenous, single-stranded, evolutionarily conserved non-coding RNAs (about 22 nucleotides in length), which play key roles in almost all biological processes including proliferation, differentiation, inflammation, and immunity [9,10,11] They negatively regulate target genes mainly through mRNA degradation and translational repression by binding to their 3ʹ untranslated regions (UTRs) [9,10,11]. Recent studies indicated that the interaction between epidermal keratinocytes and immune cells in psoriasis might be linked via microRNAs/targets axis through regulating chemokine/cytokine production [18, 19]. Such reports mentioned above provide potential insight into the psoriasis pathogenesis. This study was approved by the Ethics Committee of Peking University
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
