Laboratory of Clinical Chemistry, University of Crete Medical School, Heraklion, Crete, Greece.
FORTH, Institute of Molecular Biology and Biotechnology, Heraklion, Crete, Greece.
Front Immunol. 2019 Jun 12;10:1330. doi: 10.3389/fimmu.2019.01330. eCollection 2019.
Adaptation of the innate immune system has been recently acknowledged, explaining sustained changes of innate immune responses. Such adaptation is termed trained immunity. Trained immunity is initiated by extracellular signals that trigger a cascade of events affecting cell metabolism and mediating chromatin changes on genes that control innate immune responses. Factors demonstrated to facilitate trained immunity are pathogenic signals (fungi, bacteria, viruses) as well non-pathogenic signals such as insulin, cytokines, adipokines or hormones. These signals initiate intracellular signaling cascades that include AKT kinases and mTOR as well as histone methylases and demethylases, resulting in metabolic changes and histone modifications. In the context of insulin resistance, AKT signaling is affected resulting in sustained activation of mTORC1 and enhanced glycolysis. In macrophages elevated glycolysis readily impacts responses to pathogens (bacteria, fungi) or danger signals (TLR-driven signals of tissue damage), partly explaining insulin resistance-related pathologies. Thus, macrophages lacking insulin signaling exhibit reduced responses to pathogens and altered metabolism, suggesting that insulin resistance is a state of trained immunity. Evidence from Insulin Receptor as well as IGF1Receptor deficient macrophages support the contribution of insulin signaling in macrophage responses. In addition, clinical evidence highlights altered macrophage responses to pathogens or metabolic products in patients with systemic insulin resistance, being in concert with cell culture and animal model studies. Herein, we review the current knowledge that supports the impact of insulin signaling and other insulin resistance related signals as modulators of trained immunity.
近年来，人们已经认识到先天免疫系统的适应性，这可以解释先天免疫反应的持续变化。这种适应性被称为训练性免疫。训练性免疫是由细胞外信号引发的，这些信号引发一系列事件，影响细胞代谢，并调节控制先天免疫反应的基因的染色质变化。已证明有助于训练性免疫的因素包括致病信号（真菌、细菌、病毒）以及非致病信号，如胰岛素、细胞因子、脂肪因子或激素。这些信号启动包括 AKT 激酶和 mTOR 以及组蛋白甲基转移酶和去甲基化酶在内的细胞内信号级联反应，导致代谢变化和组蛋白修饰。在胰岛素抵抗的情况下，AKT 信号受到影响，导致 mTORC1 的持续激活和糖酵解增强。在巨噬细胞中，升高的糖酵解容易影响对病原体（细菌、真菌）或危险信号（TLR 驱动的组织损伤信号）的反应，部分解释了与胰岛素抵抗相关的病理学。因此，缺乏胰岛素信号的巨噬细胞对病原体的反应和代谢发生改变，表明胰岛素抵抗是一种训练性免疫状态。来自胰岛素受体和 IGF1 受体缺陷巨噬细胞的证据支持胰岛素信号在巨噬细胞反应中的作用。此外，临床证据强调了系统性胰岛素抵抗患者的巨噬细胞对病原体或代谢产物的反应改变，与细胞培养和动物模型研究一致。在此，我们综述了目前的知识，这些知识支持胰岛素信号和其他与胰岛素抵抗相关的信号作为训练性免疫调节剂的影响。
