Nrf2缺乏以PPARγ依赖的方式增强单核髓源性抑制细胞的免疫抑制功能。

IF 3 Q1 UROLOGY & NEPHROLOGY
Kidney360 Pub Date : 2025-09-17 DOI:10.34067/KID.0000000947
Yichen Jia, Jiawei Li, Tianying Yang, Ruimin Li, Guowei Tu, Yue Qiu, Xuepeng Zhang, Ruirui Sang, Yi Shi, Shihao Xu, Yin Celeste Cheuk, Jingjing Liu, Ruiming Rong, Yi Zhang
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引用次数: 0

摘要

背景:髓源性抑制细胞(MDSCs)包括单核细胞MDSCs (M-MDSCs)和粒细胞MDSCs (G-MDSCs),两者都能有效控制T细胞反应。尽管Nrf2参与了MDSCs的扩增和MDSC介导的免疫抑制,但Nrf2在MDSC分化中的潜在机制仍然知之甚少。方法:本研究采用流式细胞术从野生型(WT)或Nrf2-/-小鼠骨髓(BM)中诱导和分选G-MDSCs或M-MDSCs。使用小鼠肿瘤发生、急性肾损伤(AKI)和慢性肾脏疾病(CKD)模型来评估使用或不使用GW9662治疗的WT或Nrf2-/- M-MDSCs的免疫抑制功能。组织学分析评估肿瘤血管生成或肾损伤。采用免疫组化染色评价肾脏淋巴细胞浸润情况。马氏三色和天狼星红染色评价肾纤维化。此外,通过RNA测序(RNA-seq)来鉴定WT和Nrf2-/- M-MDSCs之间的基因表达差异,并使用实时PCR或western blot来验证关键发现。结果:由Nrf2-/-小鼠骨髓生成的、从Nrf2-/-荷瘤小鼠骨髓中分选的M-MDSCs的免疫抑制功能明显增强。此外,Nrf2缺失的M-MDSCs可以有效改善AKI或CKD小鼠的炎症性疾病。有趣的是,Nrf2-/- M-MDSCs的功效可能归因于诱导型一氧化氮合酶的表达增加,而精氨酸酶1的水平降低,这表明了一种非常规的激活机制。利用RNA-seq和生物信息学分析进一步的机制研究发现,过氧化物酶体增殖物激活受体-γ (PPARγ)在Nrf2-/- M-MDSCs的分化和抑制能力中发挥了重要作用,这种作用可以被GW9662(一种特异性的PPARγ抑制剂)显著阻断。结论:我们的研究结果阐明了Nrf2缺乏与M-MDSC功能相关的免疫调节机制,为Nrf2-/- M-MDSCs在炎症性疾病中的应用提供了基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Nrf2 Deficiency Enhances the Immunosuppressive Function of Monocytic Myeloid-derived Suppressor Cells in a PPARγ- Dependent Manner.

Background: Myeloid-derived suppressor cells (MDSCs) comprise monocytic MDSCs (M-MDSCs) and granulocytic MDSCs (G-MDSCs), both of which are effective for controlling T cell responses. Although Nrf2 participates in the expansion of MDSCs and MDSC-mediated immunosuppression, the underlying mechanisms of Nrf2 in MDSC differentiation remain poorly understood.

Methods: In this study, G-MDSCs or M-MDSCs were induced and sorted from the bone marrow (BM) of wild-type (WT) or Nrf2-/- mice using flow cytometry in vitro, with or without GW9662 treatment. Mouse models of tumorigenesis, acute kidney injury (AKI), and chronic kidney disease (CKD) were used to evaluate the immunosuppressive function of WT or Nrf2-/- M-MDSCs treated with or without GW9662. Histological analysis was performed to evaluate tumor angiogenesis or kidney injury. Immunohistochemical staining was used to evaluate lymphocyte infiltration in kidney. Masson's trichrome and Sirius red staining were performed to evaluate kidney fibrosis. Additionally, RNA sequencing (RNA-seq) was conducted to identify gene expression difference between WT and Nrf2-/- M-MDSCs, with real-time PCR or western blot used to validate key findings.

Results: The immunosuppressive function of M-MDSCs generated from BM of Nrf2-/- mice and sorted from Nrf2-/- tumor-bearing mice was dramatically enhanced compared to the G-MDSC counterparts. Moreover, M-MDSCs with an Nrf2 deficiency could effectively ameliorate the inflammatory disorders in mice with AKI or CKD. Intriguingly, the efficacy of Nrf2-/- M-MDSCs could be attributed to increased expression of inducible nitric oxide synthase but decreased levels of arginase 1, indicating an unconventional mechanism of activation. Further mechanistic studies using RNA-seq and bioinformatics analyses identified an essential role of peroxisome proliferator-activated receptor-γ (PPARγ) in the differentiation and suppressive ability of Nrf2-/- M-MDSCs with which the effect could be markedly blocked with GW9662, a specific PPARγ inhibitor.

Conclusions: Our findings elucidate an immunoregulatory mechanism of Nrf2 deficiency related to M-MDSC function and provides a foundation for the application of Nrf2-/- M-MDSCs in inflammatory diseases.

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来源期刊
Kidney360
Kidney360 UROLOGY & NEPHROLOGY-
CiteScore
3.90
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