Hydroxychloroquine protects against autoimmune premature ovarian insufficiency by modulating the Treg/Th17 cell ratio in BALB/c mice

Shuai, Lanjun; She, Jiajie; Diao, Ruiying; Zhao, Huihui; Liu, Xuemin; Hu, Qingyu; Li, Dongdong; Su, Danna; Ye, Xiaofeng; Guo, Yan; Zhong, Mei; Wang, Liping

doi:10.1111/aji.13686

Cited by 3 publications

(1 citation statement)

References 36 publications

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“…Consequently, decreased Toll-like receptor signaling leads to reduced dendritic cell activation and diminished interferon production [ 19 ]. In vitro experiments have shown that HCQ induces apoptosis of peripheral blood mononuclear cells, while also reducing the secretion of IL-17 factors in the peripheral blood [ 20 ] ( Fig. 1 ).…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Advancements on the impact of hydroxychloroquine in systemic lupus erythematosus

Peng-Cheng,

Meng-Na,

Jian-Bin

et al. 2024

Heliyon

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Section: Mechanisms Of Actionmentioning

confidence: 99%

Advancements on the impact of hydroxychloroquine in systemic lupus erythematosus

Peng-Cheng,

Meng-Na,

Jian-Bin

et al. 2024

Heliyon

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Human Amniotic Epithelial Stem Cells Alleviate Autoimmune Premature Ovarian Insufficiency in Mice by Targeting Granulosa Cells via AKT/ERK Pathways

Ye,

Lin,

Ying

et al. 2024

Stem Cell Rev and Rep

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Autoimmune factors play an important role in premature ovarian insufficiency (POI). Human amniotic epithelial stem cells (hAESCs) have recently shown promising treatment effects on chemotherapy-induced POI. However, the therapeutic efficacy and underlying mechanisms of hAESCs in autoimmune POI remain to be investigated. In this study, we showed for the first time that intravenous transplantation of hAESCs could reside in the ovary of zona pellucida 3 peptide (pZP3) induced autoimmune POI mice model for at least 4 weeks. hAESCs could improve ovarian function and fertility, alleviate inflammation and reduce apoptosis of granulosa cells (GCs) in autoimmune POI mice. The transcriptome analysis of mice ovaries and in vitro co-cultivation experiments suggest that activation of the AKT and ERK pathways may be the key mechanism in the therapeutic effect of hAESCs. Our work provides the theoretical and experimental foundation for optimizing the administration of hAESCs, as well as the clinical application of hAESCs in autoimmune POI patients. Graphical Abstract

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Dihydroberberine alleviates Th17/Treg imbalance in premature ovarian insufficiency mice via inhibiting Rheb/mTOR signaling

Deng,

Wu,

et al. 2024

Mol Med

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Background Premature ovarian insufficiency (POI) is an immune-related condition. Dihydroberberine (dhBBR) plays a regulatory role in maintaining the T-helper 17 (Th17)/regulatory T (Treg) cell balance. This study aimed to explore the action mechanisms of dhBBR on POI. Methods In vivo, female BALB/c mice were used as POI models, treated with dhBBR, or injected with recombinant interleukin (rIL)-17 and anti-CD25 monoclonal antibody. Hematoxylin and eosin staining was used to validate the model and assess the therapeutic effects of dhBBR. mRNA expression levels of cytochrome P450 (Cyp)-17a1, Cyp19a1, Cyp11a1, steroidogenic acute regulatory protein, and luteinizing hormone receptor in mouse ovaries were quantified via quantitative polymerase chain reaction (qPCR). Enzyme-linked immunosorbent assay was used to determine the cytokine and sex hormone levels. Immunohistochemical staining for cleaved-caspase 3 and Ki-67 were performed to assess ovarian cell apoptosis and proliferation. Flow cytometry was used to analyze the Th17/Treg cell balance in the ovary and spleen. In vitro cytotoxicity of dhBBR was measured using the cell counting kit-8 assay. GTP-Ras homolog enriched in brain (Rheb) activity was determined via immunofluorescence assay. Co-immunoprecipitation was performed to assess Rheb activity, Th17 or Treg induction, and binding between Rheb and mammalian target of rapamycin (mTOR) after dhBBR treatment. Flow cytometry and qPCR assays were used to verify the effect of dhBBR on CD4 + cell differentiation. Finally, Rheb/mTOR pathway activation was confirmed via western blotting of proteins, including mTOR, p-mTOR, p70S6K, p-p70S6K, 4E-BP1, and p-4E-BP1. Results dhBBR improved the ovarian function in a dose-dependent manner. It also decreased ovarian cell apoptosis and increased cell proliferation. It decreased Th1 and Th17 cell proportions but increased Treg cell proportions in the ovaries and spleens of POI model mice. Cell experiments revealed that dhBBR promoted CD4 + cell differentiation into Treg cells. Co-immunoprecipitation revealed Rheb as the dhBBR target that bound to mTOR. However, MHY1485 restored dhBBR-induced changes in forkhead box P3, IL-10, transforming growth factor-β1, IL-17, IL-22, retinoic acid-related orphan receptor-γt and p-mTOR levels in Th17- and Treg-induced CD4 + cells. Conclusion Overall, dhBBR targeted the Rheb/mTOR pathway to promote CD4 + cell differentiation into Treg cells and alleviate POI.

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Hydroxychloroquine protects against autoimmune premature ovarian insufficiency by modulating the Treg/Th17 cell ratio in BALB/c mice

Cited by 3 publications

References 36 publications

Advancements on the impact of hydroxychloroquine in systemic lupus erythematosus

Advancements on the impact of hydroxychloroquine in systemic lupus erythematosus

Human Amniotic Epithelial Stem Cells Alleviate Autoimmune Premature Ovarian Insufficiency in Mice by Targeting Granulosa Cells via AKT/ERK Pathways

Dihydroberberine alleviates Th17/Treg imbalance in premature ovarian insufficiency mice via inhibiting Rheb/mTOR signaling

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