The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity

Dominguez-Andres Jorge; Novakovic Boris; Li Yang; Scicluna Brendon P.; Gresnigt Mark S.; Arts Rob J. W.; Oosting Marije; Moorlag Simone J. C. F. M.; Groh Laszlo A.; Zwaag Jelle; Koch Rebecca M.; ter Horst Rob; Joosten Leo A. B.; Wijmenga Cisca; Michelucci Alessandro; van der Poll Tom; Kox Matthijs; Pickkers Peter; Kumar Vinod; Stunnenberg Henk; Netea Mihai G.

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The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity

机译：itAconate途径是一种连接先天免疫耐受性和培训的免疫力的中央调节节点

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Sepsis involves simultaneous hyperactivation of the immune system and immune paralysis, leading to both organ dysfunction and increased susceptibility to secondary infections. Acute activation of myeloid cells induced itaconate synthesis, which subsequently mediated innate immune tolerance in human monocytes. In contrast, induction of trained immunity by beta-glucan counteracted tolerance induced in a model of human endotoxemia by inhibiting the expression of immune-responsive gene 1 (IRG1), the enzyme that controls itaconate synthesis. beta-Glucan also increased the expression of succinate dehydrogenase (SDH), contributing to the integrity of the TCA cycle and leading to an enhanced innate immune response after secondary stimulation. The role of itaconate was further validated by IRG1 and SDH poly-morphisms that modulate induction of tolerance and trained immunity in human monocytes. These data demonstrate the importance of the IRG1-itaconate-SDH axis in the development of immune tolerance and training and highlight the potential of beta-glucan-induced trained immunity to revert immunoparalysis.

机译：脓毒症涉及同时同时激活免疫系统和免疫瘫痪，导致器官功能障碍和对二次感染的易感性增加。骨髓细胞急性活化诱导汽康酸盐合成，随后介导人单核细胞的先天免疫耐受性。相反，通过抑制免疫响应基因1（IRG1）的表达，通过抑制控制迭科合成的酶，通过β-葡聚糖诱导培训的免疫诱导诱导人内毒血症模型中的耐受性。 β-葡聚糖还增加了琥珀酸酯脱氢酶（SDH）的表达，有助于TCA循环的完整性，并导致继发刺激后提高先天免疫应答。 IRG1和SDH多态源进一步验证了迭科的作用，其调节诱导人单核细胞中耐受性和培训的免疫力。这些数据证明了IRG1-itAconate-SDH轴在免疫耐受性和培训开发中的重要性，并突出β-葡聚糖诱导的培训免疫力恢复免疫分析的潜力。

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《Cell metabolism》 |2019年第1期|共15页
作者
Dominguez-Andres Jorge; Novakovic Boris; Li Yang; Scicluna Brendon P.; Gresnigt Mark S.; Arts Rob J. W.; Oosting Marije; Moorlag Simone J. C. F. M.; Groh Laszlo A.; Zwaag Jelle; Koch Rebecca M.; ter Horst Rob; Joosten Leo A. B.; Wijmenga Cisca; Michelucci Alessandro; van der Poll Tom; Kox Matthijs; Pickkers Peter; Kumar Vinod; Stunnenberg Henk; Netea Mihai G.;
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Radboud Univ Nijmegen Dept Internal Med 463 Med Ctr Geert Grootepl 8 NL-6500 HB Nijmegen;

Radboud Univ Nijmegen Fac Sci Dept Mol Biol NL-6525 GA Nijmegen Netherlands;

Univ Med Ctr Groningen Dept Genet Groningen Netherlands;

Univ Amsterdam Ctr Expt &

Mol Med Amsterdam Med Ctr Div Infect Dis Amsterdam Netherlands;

Radboud Univ Nijmegen Dept Internal Med 463 Med Ctr Geert Grootepl 8 NL-6500 HB Nijmegen;

Radboud Univ Nijmegen Dept Internal Med 463 Med Ctr Geert Grootepl 8 NL-6500 HB Nijmegen;

Radboud Univ Nijmegen Dept Internal Med 463 Med Ctr Geert Grootepl 8 NL-6500 HB Nijmegen;

Radboud Univ Nijmegen Dept Internal Med 463 Med Ctr Geert Grootepl 8 NL-6500 HB Nijmegen;

Radboud Univ Nijmegen Dept Internal Med 463 Med Ctr Geert Grootepl 8 NL-6500 HB Nijmegen;

Radboud Univ Nijmegen Radboud Ctr Infect Dis RCI Med Ctr Geert Grootepl 8 NL-6500 HB Nijmegen;

Radboud Univ Nijmegen Radboud Ctr Infect Dis RCI Med Ctr Geert Grootepl 8 NL-6500 HB Nijmegen;

Radboud Univ Nijmegen Dept Internal Med 463 Med Ctr Geert Grootepl 8 NL-6500 HB Nijmegen;

Radboud Univ Nijmegen Dept Internal Med 463 Med Ctr Geert Grootepl 8 NL-6500 HB Nijmegen;

Univ Med Ctr Groningen Dept Genet Groningen Netherlands;

Luxembourg Inst Hlth Dept Oncol NORLUX Neurooncol Lab Luxembourg Luxembourg;

Univ Amsterdam Ctr Expt &

Mol Med Amsterdam Med Ctr Div Infect Dis Amsterdam Netherlands;

Radboud Univ Nijmegen Radboud Ctr Infect Dis RCI Med Ctr Geert Grootepl 8 NL-6500 HB Nijmegen;

Radboud Univ Nijmegen Radboud Ctr Infect Dis RCI Med Ctr Geert Grootepl 8 NL-6500 HB Nijmegen;

Radboud Univ Nijmegen Dept Internal Med 463 Med Ctr Geert Grootepl 8 NL-6500 HB Nijmegen;

Radboud Univ Nijmegen Fac Sci Dept Mol Biol NL-6525 GA Nijmegen Netherlands;

Radboud Univ Nijmegen Dept Internal Med 463 Med Ctr Geert Grootepl 8 NL-6500 HB Nijmegen;

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中图分类内分泌腺疾病及代谢病;
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1. The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity [J] . Dominguez-Andres Jorge, Novakovic Boris, Li Yang, Cell metabolism . 2019,第1期

机译：itAconate途径是一种连接先天免疫耐受性和培训的免疫力的中央调节节点
2. Receptors and Pathways in Innate antifungal immunity:The Implication for Tolerance and Immunity to Fungi [J] . Teresa Zelante, Claudia Montagnoli, Silvia Bozza, Advances in Experimental Medicine and Biology . 2007,第0期

机译：先天性抗真菌免疫的受体和途径：对真菌的耐受性和免疫性
3. Overcoming the hurdles of tumor immunity by targeting regulatory pathways in innate and adaptive immune cells. [J] . Zwirner NW, Croci DO, Domaica C Current pharmaceutical design . 2010,第3期

机译：通过靶向先天和适应性免疫细胞中的调控途径，克服肿瘤免疫的障碍。
4. Innate and Adaptive Immune Pathways to Tolerance [C] . Catherine A. Thornton, Gareth Morgan Nestle? Nutrition Workshop . 2009

机译：对耐受性的先天和自适应免疫途径
5. Endotoxin tolerance as a novel regulatory mechanism of the oral mucosal innate immune response during chronic periodontitis. [D] . Muthukuru, Manoj. 2005

机译：内毒素耐受性是慢性牙周炎期间口腔粘膜固有免疫反应的新型调节机制。
6. Ultrasound May Suppress Tumor Growth Inhibit Inflammation and Establish Tolerogenesis by Remodeling Innatome via Pathways of ROS Immune Checkpoints Cytokines and Trained Immunity/Tolerance [O] . Qian Yang, Ruijing Zhang, Peng Tang, 2021

机译：超声抑制肿瘤生长抑制炎症并通过ROS免疫检查点细胞因子的途径改造innatome来建立耐受性并且训练有素的免疫/耐受性
7. Trained Innate Immunity as a Novel Mechanism Linking Infection and the Development of Atherosclerosis [O] . Jenneke Leentjens, Siroon Bekkering, Leo A.B. Joosten, 2018

机译：训练有素的先天免疫作为一种连接感染和动脉粥样硬化的发展的新机制

The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity

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