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

IF 3 4区医学 Q3 IMMUNOLOGY

Immunopharmacology and Immunotoxicology Pub Date : 2025-10-01 Epub Date: 2025-09-09 DOI:10.1080/08923973.2025.2554662

Pan Huang, Yi Pan, Meijunzi Luo, Rong Zhou, Chang Wang, Haizhen Wang

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引用次数: 0

Abstract

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.

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苦参碱通过上调FOXO4使circtnfrsf21介导的JAK/STAT3轴失活，缓解特应性皮炎的免疫失衡。

目的：特应性皮炎（AD）是一种常见的慢性炎症性皮肤病。在此，我们旨在证明苦参碱（MT）对AD的疗效并揭示其作用机制。材料与方法：1-氟-2,4-二硝基苯（DNFB）外用诱导AD模型。H&E染色观察表皮组织组织学变化，ELISA法检测炎症因子表达。MTT法测定细胞活力。流式细胞术检测T细胞分化情况。通过ChIP、双荧光素酶报告基因法、RIP和RNA拉下法检测目标相互作用。结果：AD患者血清中LDH、IgE、circTNFRSF21、STAT3水平升高，FOXO4水平降低。MT可改善AD模型的表皮厚度，抑制炎症细胞和巨噬细胞浸润，降低皮炎评分。此外，MT调节T细胞的免疫失衡，减轻TNF-α/IFN-γ诱导的角质形成细胞的炎症损伤。FOXO4抑制TNFRSF21转录，从而抑制circTNFRSF21的表达。此外，circTNFRSF21被发现与ELAVL1结合，从而增强了stat3mrna的稳定性。此外，circTNFRSF21的过表达逆转了MT对TNF-α/IFN-γ诱导的HaCat损伤的作用。WP1066 （JAK/STAT3抑制剂）在MT处理的HaCat细胞中消除了circTNFRASF21过表达的作用。结论：MT通过抑制circTNFRSF21的表达，降低STAT3信号通路的活性，减轻了特应性皮炎的炎症反应。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Immunopharmacology and Immunotoxicology 医学-毒理学

CiteScore

5.40

自引率

0.00%

发文量

133

审稿时长

4-8 weeks

期刊介绍： The journal Immunopharmacology and Immunotoxicology is devoted to pre-clinical and clinical drug discovery and development targeting the immune system. Research related to the immunoregulatory effects of various compounds, including small-molecule drugs and biologics, on immunocompetent cells and immune responses, as well as the immunotoxicity exerted by xenobiotics and drugs. Only research that describe the mechanisms of specific compounds (not extracts) is of interest to the journal. The journal will prioritise preclinical and clinical studies on immunotherapy of disorders such as chronic inflammation, allergy, autoimmunity, cancer etc. The effects of small-drugs, vaccines and biologics against central immunological targets as well as cell-based therapy, including dendritic cell therapy, T cell adoptive transfer and stem cell therapy, are topics of particular interest. Publications pointing towards potential new drug targets within the immune system or novel technology for immunopharmacological drug development are also welcome. With an immunoscience focus on drug development, immunotherapy and toxicology, the journal will cover areas such as infection, allergy, inflammation, tumor immunology, degenerative disorders, immunodeficiencies, neurology, atherosclerosis and more. Immunopharmacology and Immunotoxicology will accept original manuscripts, brief communications, commentaries, mini-reviews, reviews, clinical trials and clinical cases, on the condition that the results reported are based on original, clinical, or basic research that has not been published elsewhere in any journal in any language (except in abstract form relating to paper communicated to scientific meetings and symposiums).