Gorin Aleksandr, Harriott Noa, Koduvayur Vyas, Cheng Quen J, Hoffmann Alexander
Department of Medicine, Division of Infectious Diseases, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
bioRxiv. 2025 Jul 1:2025.06.12.659073. doi: 10.1101/2025.06.12.659073.
Macrophages, as key sentinel cells of the innate immune system, can retain memory of prior stimulus exposure. Interferon gamma (IFNγ) plays a central role in maintaining trained immunity and can induce potent memory in macrophages. Such memory is associated with the formation of enhancers that alter gene expression responses to subsequent stimuli. However, how such enhancers are maintained after cytokine exposure remains unclear. We report that durable IFNγ-induced enhancers can last for days after cytokine washout, yet the underlying persistence mechanism is not cell-intrinsic. IFNγ-treated macrophages continue to exhibit JAK/STAT signaling days after cytokine removal. Blocking IFNγ signaling with a JAK inhibitor or anti-IFNγ neutralizing antibodies after cytokine removal is sufficient to reverse IFNγ-induced enhancers and erase the potentiated state of the treated macrophages. Our findings suggest that epigenetic changes in macrophages do not inherently encode innate immune memory or a "potentiated" macrophage state, but in fact are themselves dependent on ongoing cytokine signaling. These findings suggest new possibilities for pharmacologic interventions to reverse aberrantly trained immune states associated with pathology.
巨噬细胞作为固有免疫系统的关键哨兵细胞，能够保留对先前刺激暴露的记忆。干扰素γ（IFNγ）在维持训练有素的免疫中起核心作用，并且能够在巨噬细胞中诱导强大的记忆。这种记忆与增强子的形成有关，这些增强子会改变基因对后续刺激的表达反应。然而，细胞因子暴露后这些增强子是如何维持的仍不清楚。我们报告称，持久的IFNγ诱导的增强子在细胞因子洗脱后可持续数天，但其潜在的持续机制并非细胞内在的。细胞因子去除数天后，经IFNγ处理的巨噬细胞仍继续表现出JAK/STAT信号传导。细胞因子去除后用JAK抑制剂或抗IFNγ中和抗体阻断IFNγ信号传导足以逆转IFNγ诱导的增强子并消除处理过的巨噬细胞的增强状态。我们的研究结果表明，巨噬细胞中的表观遗传变化并非固有地编码固有免疫记忆或“增强”的巨噬细胞状态，实际上它们本身依赖于持续的细胞因子信号传导。这些发现为逆转与病理学相关的异常训练免疫状态的药物干预提供了新的可能性。
