Matrine alleviates the immune imbalance of atopic dermatitis by up-regulating FOXO4 to inactivate circTNFRSF21-mediated JAK/STAT3 axis

Objective: Atopic dermatitis (AD) is a common chronic inflammatory skin problem. Herein, we aimed to demonstrate the efficacy of matrine (MT) on AD and to reveal its mechanism.

Material and methods: An AD model was induced via topical administration of 1-fluoro-2,4-dinitorobenzene (DNFB). H&E staining was performed to observe the histological alterations of epidermal tissue, and the expression of inflammatory cytokines were measured using ELISA assay. Cell viability was determined using MTT assay. The T cell differentiation was monitored by flow cytometry. The target interactions were detected by ChIP, dual luciferase reporter assays, RIP, and RNA pull down assays.

Results: LDH, IgE, circTNFRSF21, and STAT3 levels in the serum of AD patients were elevated, while FOXO4 was decreased. Treatment with MT improved epidermal thickness in AD models, suppressed inflammatory cell and macrophage infiltration, and reduced the dermatitis score. Additionally, MT regulated the immune imbalance of T cells to mitigate the inflammatory damage on keratinocytes induced by TNF-α/IFN-γ. FOXO4 inhibited TNFRSF21 transcription to suppress circTNFRSF21 expression. Moreover, circTNFRSF21 was found to bind to ELAVL1, thereby enhancing STAT3 mRNA stability. In addition, overexpression of circTNFRSF21 reversed the effect of MT on TNF-α/IFN-γ induced HaCat injury. WP1066 (JAK/STAT3 Inhibitor) eliminated the role of circTNFRASF21 overexpression in MT treated HaCat cells.

Conclusion: MT alleviates the inflammatory response of atopic dermatitis by suppressing circTNFRSF21 expression to decrease the activity of STAT3 signaling pathway.

Atopic dermatitis; STAT3; circTNFRSF21; immune imbalance; inflammation.