HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, USA.
Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, New York, USA.
Immunol Rev. 2024 May;323(1):257-275. doi: 10.1111/imr.13330. Epub 2024 Apr 3.
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.
先天免疫细胞的训练和启动涉及到 PAMPs、DAMPs 和/或细胞因子的预处理，这些预处理在二次挑战时会引发更强的炎症基因诱导。以前的模型基于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，其中强烈的刺激会导致对二次挑战的抵抗力。训练和启动对于先天记忆反应很重要，这些反应可以预防感染、疫苗的有效性，并使先天免疫细胞保持准备状态；耐受可防止过度免疫激活的毒性。这些过程的失调可能导致自身免疫/炎症疾病、COVID-19 后过度炎症状态或与败血症相关的免疫麻痹的发病机制。训练、启动和耐受调节相似的“特征”炎症基因，如 TNF、IL6 和 IL1B，并利用重叠的表观遗传机制。我们回顾了干扰素（IFNs）如何通过染色质介导的机制在调节训练、启动和耐受方面发挥关键作用，干扰素以激活 JAK-STAT 信号和干扰素刺激基因而闻名。我们提出了新的数据，说明单核细胞向巨噬细胞分化如何调节 IFN-γ介导的启动，影响 AP-1 和 CEBP 活性的调节，并减弱炎症基因的过度诱导。我们提出了一个“训练-启动连续体”模型，该模型将 IFN 介导的启动纳入到关于训练和耐受的现有概念中，并提出了 STAT1 和 IRF1 的核心作用。
