α-Ketoglutarate–Dependent KDM6 Histone Demethylases and Interferon-Stimulated Gene Expression in Lupus

IF 11.4 1区医学 Q1 RHEUMATOLOGY

Arthritis & Rheumatology Pub Date : 2023-10-06 DOI:10.1002/art.42724

Erica N. Montano, Moumita Bose, Lihong Huo, Gantsetseg Tumurkhuu, Gabriela De Los Santos, Brianna Simental, Aleksandr B. Stotland, Janet Wei, C. Noel Bairey Merz, Jo Suda, Gislaine Martins, Sarfaraz Lalani, Kate Lawrenson, Yizhou Wang, Sarah Parker, Swamy Venuturupalli, Mariko Ishimori, Daniel J. Wallace, Caroline A. Jefferies

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Abstract

Objective

We aimed to investigate the hypothesis that interferon (IFN)–stimulated gene (ISG) expression in systemic lupus erythematosus (SLE) monocytes is linked to changes in metabolic reprogramming and epigenetic regulation of ISG expression.

Methods

Monocytes from healthy volunteers and patients with SLE at baseline or following IFNα treatment were analyzed by extracellular flux analysis, proteomics, metabolomics, chromatin immunoprecipitation, and gene expression. The histone demethylases KDM6A/B were inhibited using glycogen synthase kinase J4 (GSK-J4). GSK-J4 was tested in pristane and resiquimod (R848) models of IFN-driven SLE.

Results

SLE monocytes had enhanced rates of glycolysis and oxidative phosphorylation compared to healthy control monocytes, as well as increased levels of isocitrate dehydrogenase and its product, α-ketoglutarate (α-KG). Because α-KG is a required cofactor for histone demethylases KDM6A and KDM6B, we hypothesized that IFNα may be driving “trained immune” responses through altering histone methylation. IFNα priming (day 1) resulted in a sustained increase in the expression of ISGs in primed cells (day 5) and enhanced expression on restimulation with IFNα. Importantly, decreased H3K27 trimethylation was observed at the promoters of ISGs following IFNα priming. Finally, GSK-J4 (KDM6A/B inhibitor) resulted in decreased ISG expression in SLE patient monocytes, as well as reduced autoantibody production, ISG expression, and kidney pathology in R848-treated BALB/c mice.

Conclusion

Our study suggests long-term IFNα exposure alters the epigenetic regulation of ISG expression in SLE monocytes via changes in immunometabolism, a mechanism reflecting trained immunity to type I IFN. Importantly, it opens the possibility that targeting histone-modifying enzymes, such as KDM6A/B, may reduce IFN responses in SLE.

Abstract Image

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α-酮戊二酸依赖性KDM6组蛋白去甲基化酶调节狼疮中干扰素刺激基因的表达。

目的：探讨系统性红斑狼疮（SLE）单核细胞干扰素（IFN）刺激基因（ISG）表达与代谢重编程和ISG表达表观遗传学调控的变化有关的假说。方法：通过细胞外流量分析、蛋白质组学、代谢组学、染色质免疫沉淀和基因表达分析健康志愿者和SLE患者在IFNα治疗前后的单核细胞。GSK-J4抑制组蛋白去甲基化酶KDM6A/B。GSK-J4在干扰素驱动的SLE的pristane和resiquimod（R848）模型中进行了测试。结果：与健康对照（HC）单核细胞相比，SLE单核细胞的糖酵解和氧化磷酸化速率提高，异柠檬酸脱氢酶（IDH2）及其产物α-酮戊二酸（α-KG）水平升高。由于α-KG是组蛋白去甲基化酶KDM6A和KDM6B所需的辅因子，我们假设IFNα可能通过改变组蛋白甲基化来驱动“训练的免疫”反应。IFNα启动（第1天）导致启动细胞中ISG的表达持续增加（第5天），并在用IFNα再刺激时增强表达。重要的是，在IFNα引发后，在ISG的启动子处观察到H3K27三甲基化减少。最后，GSK-J4（KDM6A/B抑制剂）导致SLE患者单核细胞中ISG表达降低，以及R848治疗的Balb/c小鼠的自身抗体产生、ISG表达和肾脏病理学降低。结论：我们的研究表明，慢性IFNα暴露通过免疫代谢的变化改变了SLE单核细胞ISG表达的表观遗传学调节，这是一种反映对I型IFN训练免疫的机制。重要的是，它开启了靶向组蛋白修饰酶（如KDM6A/B）可能减少SLE中IFN反应的可能性。

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

Arthritis & Rheumatology RHEUMATOLOGY-

CiteScore

20.90

自引率

3.00%

发文量

371

期刊介绍： Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.