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Published on: October 6, 2019
miR‑155 promotes an inflammatory response in HaCaT cells via the IRF2BP2/KLF2/NF‑κB pathway in psoriasis
Lu Chen1, Chang Liu1, Xuesong Xiang1
1Department of Immunology, School of Medicine, Jianghan University, Wuhan, Hubei 430056, P.R. China.
Abstract:
Psoriasis is a chronic inflammatory skin condition with numerous causes, including genetic, immunological and infectious factors. The course of psoriasis is long and recurrence is common; pathogenesis is not completely understood. However, there is an association between advancement of psoriasis and aberrant microRNA (miR or miRNA)‑155 expression. Through bioinformatics, the present study aimed to analyze the differentially expressed genes and miRNAs in psoriasis and its biological mechanism and function psoriatic inflammation. First of all, differentially expressed genes (DEGs) and miRNAs (DEMs) in patients with psoriasis were identified using GEO2R interactive web application. A psoriasis inflammatory model was established using lipopolysaccharide (LPS)‑treated HaCaT keratinocytes, which were transfected with miR‑155 mimic or inhibitor. Cell Counting Kit‑8 was used for the assessment of cell viability and proliferation, and changes in the cell cycle were examined using flow cytometry. ELISA and reverse transcription‑quantitative PCR (RT‑qPCR) were used to detect the expression levels of the inflammatory factors IL‑1β and IL‑6. The dual‑luciferase reporter assay was used to verify the targeting association between miR‑155‑5p and IFN regulatory factor 2 binding protein 2 (IRF2BP2). To verify the targeting association of miR‑155 and the IRF2BP2/kruppel‑like factor 2 (KLF2)/NF‑κB signaling pathway, expression levels of IRF2BP2, KLF2 and p65 were identified by RT‑qPCR and western blotting. IRF2BP2 levels were also confirmed by immunofluorescence, in conjunction with bioinformatics database analysis. Overexpression of miR‑155 inhibited proliferation of HaCaT cells and increased the number of cells in S phase and decreasing number of cells in G1 and G2 phase. In the LPS‑induced inflammatory state, miR‑155 overexpression heightened the inflammatory response of HaCaT cells while inhibition of miR‑155 lessened it. Suppression of inflammatory cytokine expression by miR‑155‑5p inhibitor was reversed by knockdown of IRF2BP2. miR‑155 was shown to interact with IRF2BP2 to negatively regulate its expression, leading to decreased KLF2 expression and increased p65 expression and secretion of inflammatory factors, intensifying the inflammatory response of HaCaT cells. Therefore, miR‑155 may contribute to development of psoriasis by inducing tissue and cell damage by increasing the inflammatory response of HaCaT cells via the IRF2BP2/KLF2/NF‑κB pathway. In conclusion, the results of the present study offer novel perspectives on the role of miR‑155 in the onset and progression of psoriasis.
Insights
MicroRNA-155 (miR-155) exacerbates psoriasis by promoting inflammation through the IRF2BP2/KLF2/NF-κB pathway. Inhibiting miR-155 may offer a therapeutic strategy for psoriasis by reducing inflammatory responses.
Area of Science:
- Dermatology
- Molecular Biology
- Immunology
Background:
- Psoriasis is a chronic inflammatory skin disease with complex pathogenesis.
- Aberrant microRNA (miRNA) expression, particularly miR-155, is linked to psoriasis development.
- The precise molecular mechanisms underlying miR-155's role in psoriatic inflammation require further elucidation.
Purpose of the Study:
- To investigate the role of differentially expressed genes and miRNAs in psoriasis.
- To analyze the biological mechanisms and functions of miR-155 in psoriatic inflammation.
- To explore the potential therapeutic targeting of miR-155 in psoriasis.
Main Methods:
- Bioinformatic analysis of gene and miRNA expression data in psoriasis patients.
- Establishment of a lipopolysaccharide (LPS)-induced HaCaT keratinocyte model for psoriasis.
- Transfection with miR-155 mimic or inhibitor, followed by cell viability, cell cycle, inflammatory cytokine (IL-1β, IL-6) assays, and dual-luciferase reporter assays.
- Validation of the miR-155 targeting of IRF2BP2 and its downstream effects on the IRF2BP2/KLF2/NF-κB pathway using RT-qPCR, western blotting, and immunofluorescence.
Main Results:
- Overexpression of miR-155 inhibited HaCaT cell proliferation and altered cell cycle distribution.
- In LPS-treated cells, miR-155 overexpression intensified inflammation, while inhibition reduced it.
- miR-155 directly targets IRF2BP2, leading to decreased KLF2 and increased p65 expression, thereby promoting inflammatory responses via the IRF2BP2/KLF2/NF-κB pathway.
- Knockdown of IRF2BP2 reversed the anti-inflammatory effects of miR-155 inhibition.
Conclusions:
- miR-155 plays a significant role in promoting psoriatic inflammation by negatively regulating IRF2BP2 expression.
- The miR-155/IRF2BP2/KLF2/NF-κB axis is a key pathway contributing to psoriasis pathogenesis.
- Targeting miR-155 presents a potential therapeutic strategy for managing psoriasis by mitigating inflammation and tissue damage.
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