The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity
The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity
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DOI：
10.1016/j.cmet.2018.09.003
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发表时间：
2019-01-08
期刊：
影响因子：
29
通讯作者：
Netea, Mihai G.
中科院分区：
文献类型：
--
作者：
Dominguez-Andres, Jorge;Novakovic, Boris;Netea, Mihai G.
脓毒症涉及免疫系统同时过度激活和免疫瘫痪，导致器官功能障碍和增加继发感染的易感性。髓系细胞的急性激活诱导了衣康酸的合成，随后介导了人单核细胞的天然免疫耐受。相比之下，β-葡聚糖诱导的训练性免疫通过抑制免疫反应基因1(IRG1)的表达来抵消在人类内毒素血症模型中诱导的耐受性，IRG1是控制衣康酸合成的酶。β-葡聚糖还增加琥珀酸脱氢酶(SDH)的表达，有助于TCA循环的完整性，并导致二次刺激后的天然免疫反应增强。衣康酸的作用被IRG1和SDH多态进一步证实，这些多态调节人类单核细胞耐受和训练免疫的诱导。这些数据证明了IRG1-衣康酸-SDH轴在免疫耐受和训练的发展中的重要性，并突出了β-葡聚糖诱导的训练免疫逆转免疫麻痹的潜力。
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.