Sterile tissue injury is thought to locally activate innate immune responses via damage-associated molecular patterns (DAMPs). Whether innate immune pathways are remotely activated remains relatively unexplored. Here, by analyzing ~145,000 single-cell transcriptomes at steady state and after myocardial infarction (MI) in mice and humans, we show that the type I interferon (IFN) response, characterized by expression of IFN-stimulated genes (ISGs), begins far from the site of injury, in neutrophil and monocyte progenitors within the bone marrow. In the peripheral blood of patients, we observed defined subsets of ISG-expressing neutrophils and monocytes. In the bone marrow and blood of mice, ISG expression was detected in neutrophils and monocytes and their progenitors, intensified with maturation at steady-state and after MI, and was controlled by Tet2 and Irf3 transcriptional regulators. Within the infarcted heart, ISG-expressing cells were negatively regulated by Nrf2 activation in Ccr2⁻ steady-state cardiac macrophages. Our results show that IFN signaling begins in the bone marrow, implicate multiple transcriptional regulators (Tet2, Irf3, and Nrf2) in governing ISG expression, and provide a clinical biomarker (ISG score) for studying IFN signaling in patients.

无菌组织损伤被认为通过损伤相关分子模式 (DAMP) 局部激活先天免疫反应。先天免疫途径是否被远程激活仍然相对未探索。在这里，通过分析小鼠和人类在稳态和心肌梗死 (MI) 后的约 145,000 个单细胞转录组，我们发现以 IFN 刺激基因 (ISG) 的表达为特征的 I 型干扰素 (IFN) 反应开始远离损伤部位，在骨髓内的中性粒细胞和单核细胞祖细胞中。在患者的外周血中，我们观察到表达 ISG 的中性粒细胞和单核细胞的定义亚群。在小鼠的骨髓和血液中，在中性粒细胞和单核细胞及其祖细胞中检测到 ISG 表达，在稳态和 MI 后随着成熟而增强，并由 Tet2 和 Irf3 转录调节因子控制。在梗塞的心脏内，表达 ISG 的细胞受到 Ccr2 中 Nrf2 激活的负调控⁻稳态心脏巨噬细胞。我们的研究结果表明，IFN 信号传导始于骨髓，涉及多个转录调节因子（Tet2、Irf3 和 Nrf2）控制 ISG 表达，并为研究患者的 IFN 信号传导提供临床生物标志物（ISG 评分）。