Berberine alleviates diabetic retinopathy by regulating the Th17/Treg ratio

IF 3.3 4区医学 Q3 IMMUNOLOGY

Immunology letters Pub Date : 2024-05-01 DOI:10.1016/j.imlet.2024.106862

Yi Yang , Zexin Wen , Yanli Zhang , Pengfei Li , Junyao Zhao , Yujie Sun , Peng Wang , Wei Lin

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引用次数: 0

Abstract

Background

Diabetic retinopathy (DR) stands as a prominent complication of diabetes. Berberine (BBR) has reported to be effective to ameliorate the retinal damage of DR. Studying the potential immunological mechanisms of BBR on the streptozotocin (STZ) induced DR mouse model will explain the therapeutic mechanisms of BBR and provide theoretical basis for the clinical application of this drug.

Methods

C57BL/6 J mice were induced into a diabetic state using a 50 mg/(kg·d) dose of STZ over a 5-day period. Subsequently, they were subjected to a high-fat diet (HFD) for one month. Following a 5-week treatment with 100 mg/(kg·d) BBR, the concentrations of inflammatory factors in the mice's peripheral blood were determined using an enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin staining was employed to scrutinize pathological changes in the mice's retinas, while flow cytometry assessed the proportions of T-lymphocyte subsets and the activation status of dendritic cells (DCs) in the spleen and lymph nodes. CD4⁺T cells and DC2.4 cell lines were utilized to investigate the direct and indirect effects of BBR on T cells under high glucose conditions in vitro.

Results

Following 5 weeks of BBR treatment in the streptozotocin (STZ) mouse model of DR, we observed alleviation of retinal lesions and a down-regulation in the secretion of inflammatory cytokines, namely TNF-α, IL-1β, and IL-6, in the serum of these mice. And in the spleen and lymph nodes of these mice, BBR inhibited the proportion of Th17 cells and promoted the proportion of Treg cells, thereby down-regulating the Th17/Treg ratio. Additionally, in vitro experiments, BBR directly inhibited the expression of the transcription factor RORγt and promoted the expression of the transcription factor Foxp3 in T cells, resulting in a down-regulation of the Th17/Treg ratio. Furthermore, BBR indirectly modulated the Th17/Treg ratio by suppressing the secretion of TNF-α, IL-1β, and IL-6 by DCs and enhancing the secretion of indoleamine 2,3-dioxygenase (IDO) and transforming growth factor-beta (TGF-β) by DCs. This dual action inhibited Th17 cell differentiation while promoting Treg cells.

Conclusion

Our findings indicate that BBR regulate T cell subpopulation differentiation, reducing the Th17/Treg ratio by directly or indirectly pathway. This represents a potential therapeutic avenue of BBR for improving diabetic retinopathy.

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小檗碱通过调节 Th17/Treg 的比例减轻糖尿病视网膜病变。

背景：糖尿病视网膜病变（DR糖尿病视网膜病变（DR）是糖尿病的主要并发症之一。据报道，小檗碱（BBR）可有效改善 DR 的视网膜损伤。研究小檗碱在链脲佐菌素（STZ）诱导的 DR 小鼠模型中的潜在免疫学机制将解释小檗碱的治疗机制，并为该药物的临床应用提供理论依据：方法：用 50 mg/（kg-d）剂量的 STZ 诱导 C57BL/6J 小鼠进入糖尿病状态，为期 5 天。随后，对小鼠进行为期一个月的高脂饮食（HFD）。用 100 mg/（kg-d）BBR 治疗 5 周后，用酶联免疫吸附试验（ELISA）测定小鼠外周血中的炎症因子浓度。血红素-伊红染色法可仔细检查小鼠视网膜的病理变化，流式细胞术则可评估脾脏和淋巴结中 T 淋巴细胞亚群的比例以及树突状细胞（DC）的活化状态。利用CD4+T细胞和DC2.4细胞系研究了BBR在体外高糖条件下对T细胞的直接和间接影响：结果：在链脲佐菌素（STZ）DR 小鼠模型中使用 BBR 治疗 5 周后，我们观察到小鼠视网膜病变减轻，血清中的炎性细胞因子（即 TNF-α、IL-1β 和 IL-6）分泌下调。在这些小鼠的脾脏和淋巴结中，BBR抑制了Th17细胞的比例，促进了Treg细胞的比例，从而下调了Th17/Treg的比例。此外，在体外实验中，BBR 直接抑制了 T 细胞中转录因子 RORγt 的表达，促进了转录因子 Foxp3 的表达，从而下调了 Th17/Treg 的比例。此外，BBR 还能抑制直流细胞分泌 TNF-α、IL-1β 和 IL-6，并增强直流细胞分泌吲哚胺 2,3-二氧化酶（IDO）和转化生长因子-β（TGF-β），从而间接调节 Th17/Treg 的比例。这种双重作用抑制了 Th17 细胞的分化，同时促进了 Treg 细胞的分化：我们的研究结果表明，BBR 可调节 T 细胞亚群的分化，通过直接或间接途径降低 Th17/Treg 细胞的比例。这代表了 BBR 改善糖尿病视网膜病变的潜在治疗途径。

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

Immunology letters 医学-免疫学

CiteScore

7.60

自引率

0.00%

发文量

审稿时长

44 days

期刊介绍： Immunology Letters provides a vehicle for the speedy publication of experimental papers, (mini)Reviews and Letters to the Editor addressing all aspects of molecular and cellular immunology. The essential criteria for publication will be clarity, experimental soundness and novelty. Results contradictory to current accepted thinking or ideas divergent from actual dogmas will be considered for publication provided that they are based on solid experimental findings. Preference will be given to papers of immediate importance to other investigators, either by their experimental data, new ideas or new methodology. Scientific correspondence to the Editor-in-Chief related to the published papers may also be accepted provided that they are short and scientifically relevant to the papers mentioned, in order to provide a continuing forum for discussion.