Interferons and epigenetic mechanisms in training, priming and tolerance of monocytes and hematopoietic progenitors

IF 7.5 2区 医学 Q1 IMMUNOLOGY
Bikash Mishra, Lionel B. Ivashkiv
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引用次数: 0

Abstract

Training and priming of innate immune cells involve preconditioning by PAMPs, DAMPs, and/or cytokines that elicits stronger induction of inflammatory genes upon secondary challenge. Previous models distinguish training and priming based upon whether immune activation returns to baseline prior to secondary challenge. Tolerance is a protective mechanism whereby potent stimuli induce refractoriness to secondary challenge. Training and priming are important for innate memory responses that protect against infection, efficacy of vaccines, and maintaining innate immune cells in a state of readiness; tolerance prevents toxicity from excessive immune activation. Dysregulation of these processes can contribute to pathogenesis of autoimmune/inflammatory conditions, post-COVID-19 hyperinflammatory states, or sepsis-associated immunoparalysis. Training, priming, and tolerance regulate similar “signature” inflammatory genes such as TNF, IL6, and IL1B and utilize overlapping epigenetic mechanisms. We review how interferons (IFNs), best known for activating JAK–STAT signaling and interferon-stimulated genes, also play a key role in regulating training, priming, and tolerance via chromatin-mediated mechanisms. We present new data on how monocyte-to-macrophage differentiation modulates IFN-γ-mediated priming, affects regulation of AP-1 and CEBP activity, and attenuates superinduction of inflammatory genes. We present a “training-priming continuum” model that integrates IFN-mediated priming into current concepts about training and tolerance and proposes a central role for STAT1 and IRF1.

单核细胞和造血祖细胞训练、启蒙和耐受中的干扰素和表观遗传机制
摘要先天性免疫细胞的训练和诱导涉及 PAMPs、DAMPs 和/或细胞因子的预处理,在二次挑战时会诱发更强的炎症基因。以往的模型根据免疫激活是否在二次挑战前恢复到基线来区分训练和启动。耐受是一种保护机制,通过这种机制,强刺激可诱发对二次挑战的耐受性。训练和诱导对于保护机体免受感染的先天性免疫记忆反应、疫苗的有效性以及将先天性免疫细胞维持在准备状态都非常重要;耐受可防止过度免疫激活产生毒性。这些过程的失调可能会导致自身免疫/炎症、COVID-19 后高炎症状态或败血症相关免疫分析的发病。训练、诱导和耐受调节类似的 "标志性 "炎症基因,如 TNF、IL6 和 IL1B,并利用重叠的表观遗传机制。我们回顾了以激活 JAK-STAT 信号和干扰素刺激基因而著称的干扰素(IFNs)是如何通过染色质介导的机制在调节训练、诱导和耐受中发挥关键作用的。我们提供了有关单核细胞向巨噬细胞分化如何调节 IFN-γ 介导的诱导、影响 AP-1 和 CEBP 活性调节以及减弱炎症基因超诱导的新数据。我们提出了一个 "训练-诱导连续体 "模型,该模型将 IFN 介导的诱导纳入了当前有关训练和耐受性的概念中,并提出了 STAT1 和 IRF1 的核心作用。
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来源期刊
Immunological Reviews
Immunological Reviews 医学-免疫学
CiteScore
16.20
自引率
1.10%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Immunological Reviews is a specialized journal that focuses on various aspects of immunological research. It encompasses a wide range of topics, such as clinical immunology, experimental immunology, and investigations related to allergy and the immune system. The journal follows a unique approach where each volume is dedicated solely to a specific area of immunological research. However, collectively, these volumes aim to offer an extensive and up-to-date overview of the latest advancements in basic immunology and their practical implications in clinical settings.
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