RORα negatively regulates BCG-induced trained immunity

IF 3.7 4区 医学 Q2 CELL BIOLOGY
Gizem Kilic , Vasiliki Matzaraki , Ozlem Bulut , Ilayda Baydemir , Anaisa V. Ferreira , Katrin Rabold , Simone J.C.F.M. Moorlag , Valerie A.C.M. Koeken , L. Charlotte J. de Bree , Vera P. Mourits , Leo A.B. Joosten , Jorge Domínguez-Andrés , Mihai G. Netea
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Abstract

Trained immunity is a long-lasting change in the responsiveness of innate immune cells, leading to a stronger response upon an unrelated secondary challenge. Epigenetic, transcriptional, and metabolic reprogramming contribute to the development of trained immunity. By investigating the impact of gene variants on trained immunity responses after Bacillus Calmette–Guérin (BCG) vaccination, we identified a strong association between polymorphisms in the RORA gene and BCG-induced trained immunity in PBMCs isolated from healthy human donors. RORα, encoded by the RORA gene in humans, is a nuclear receptor and a transcription factor, regulating genes involved in circadian rhythm, inflammation, cholesterol, and lipid metabolism. We found that natural RORα agonists in the circulation negatively correlate with the strength of trained immunity responses after BCG vaccination. Moreover, pharmacological inhibition of RORα in human PBMCs led to higher cytokine production capacity and boosted trained immunity induction by BCG. Blocking RORα activity also resulted in morphological changes and increased ROS and lactate production of BCG-trained cells. Blocking lactate dehydrogenase A (LDHA) and glycolysis with sodium oxamate reduced the cytokine production capacity of cells trained with a combination of BCG and the RORα agonist. In conclusion, this study highlights the potential role of RORα in trained immunity, and its impact on human vaccination and diseases should be further investigated.

Abstract Image

RORα 负向调节卡介苗诱导的训练有素的免疫力
训练有素的免疫力是先天性免疫细胞的反应能力发生的一种持久变化,它能在遇到无关的二次挑战时产生更强的反应。表观遗传、转录和代谢重编程有助于训练免疫的发展。通过研究基因变异对接种卡介苗(BCG)后训练有素的免疫反应的影响,我们发现在从健康人供体分离的白细胞介体中,RORA 基因的多态性与卡介苗诱导的训练有素的免疫反应之间存在密切联系。由人类 RORA 基因编码的 RORα 是一种核受体,也是一种转录因子,可调节涉及昼夜节律、炎症、胆固醇和脂质代谢的基因。我们发现,血液循环中的天然 RORα 激动剂与卡介苗接种后训练有素的免疫反应强度呈负相关。此外,药理抑制人PBMCs中的RORα可提高细胞因子的生产能力,并增强卡介苗诱导的训练免疫。阻断 RORα 的活性也会导致卡介苗训练细胞的形态发生变化,并增加 ROS 和乳酸的产生。用草甘膦酸钠阻断乳酸脱氢酶 A(LDHA)和糖酵解可降低卡介苗和 RORα 激动剂联合训练细胞产生细胞因子的能力。总之,本研究强调了 RORα 在训练免疫中的潜在作用,其对人类疫苗接种和疾病的影响有待进一步研究。
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来源期刊
Cellular immunology
Cellular immunology 生物-免疫学
CiteScore
8.20
自引率
2.30%
发文量
102
审稿时长
30 days
期刊介绍: Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered. Research Areas include: • Antigen receptor sites • Autoimmunity • Delayed-type hypersensitivity or cellular immunity • Immunologic deficiency states and their reconstitution • Immunologic surveillance and tumor immunity • Immunomodulation • Immunotherapy • Lymphokines and cytokines • Nonantibody immunity • Parasite immunology • Resistance to intracellular microbial and viral infection • Thymus and lymphocyte immunobiology • Transplantation immunology • Tumor immunity.
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