Berberine alleviates diabetic retinopathy by regulating the Th17/Treg ratio

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

doi:10.1016/j.imlet.2024.106862

Berberine alleviates diabetic retinopathy by regulating the Th17/Treg ratio

Immunol Lett. 2024 May 1:267:106862. doi: 10.1016/j.imlet.2024.106862. Online ahead of print.

Authors

Yi Yang¹, Zexin Wen¹, Yanli Zhang¹, Pengfei Li², Junyao Zhao³, Yujie Sun³, Peng Wang³, Wei Lin⁴

Affiliations

¹ Department of Medicine, Xizang Minzu University, Xianyang 712082, Shaanxi, PR China.
² School of Medicine, Xinjiang Tarim University, Alar 843300, Xinjiang, PR China.
³ Department of Public scientific research platform, School of clinical and basic medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250017, Shandong, PR China.
⁴ Department of Public scientific research platform, School of clinical and basic medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250017, Shandong, PR China; Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250017, Shandong, PR China; Department of Critical-care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250017, Shandong, PR China. Electronic address: weilin11@fudan.edu.cn.

PMID: 38702033
DOI: 10.1016/j.imlet.2024.106862

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.

Keywords: Berberine; Dendritic Cells; Diabetic retinopathy; T Lymphocyte Subsets.