Inflammatory responses must be tightly coordinated with the activation of emergency myelopoiesis to produce potent myeloid cells that fight infection without causing excessive host damage. Here, we show that granulocyte-macrophage colony stimulating factor (GM-CSF) programs myeloid-committed progenitors to produce trained macrophages (increased cytokine response), but programs the upstream noncommitted LKS progenitors (defined as Lin c-Kit Sca-1 cells) to produce tolerized macrophages (decreased cytokine response). In myeloid progenitors, GM-CSF strongly activates signal transducer and activator of transcription 5 (STAT5), Ras-Raf-extracellular signal regulated kinase (ERK), and Akt-mTOR signaling pathways, which are essential to establish a training program, whereas in LKS progenitors, GM-CSF induces NF-κB translocation to the nucleus to establish a tolerization program. These differences arise from higher GM-CSF receptor expression in myeloid progenitors compared with LKS cells. We demonstrate that β-catenin regulation of NF-κB nuclear translocation is central in this process. In myeloid progenitors, glycogen synthase kinase 3 (GSK3) inactivation by strong ERK and phosphatidylinositol 3 kinase (PI3K)-Akt signaling increases cytoplasmic β-catenin levels to block NF-κB nuclear translocation. In contrast, when ERK and PI3K-Akt signaling are weak, active GSK3 causes a decrease in β-catenin, allowing NF-κB nuclear translocation in LKS progenitors. Finally, GM-CSF-induced LKS tolerization takes place in several murine models of trained immunity and in human CD34 CD38 progenitors. Our study reveals that in addition to activating myelopoiesis, GM-CSF also programs early and immediate myeloid progenitors to produce opposing immune memory phenotypes. We propose that the inflammatory response from immediate myeloid progenitors may be balanced by the tolerized phenotype of early progenitors, thus providing a mechanism for appropriate resolution of inflammation and protection against a prolonged cytokine storm.

中文翻译：

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GM-CSF受体表达决定了骨髓生成不同阶段的相反的先天记忆表型


炎症反应必须与紧急骨髓生成的激活紧密协调，以产生有效的骨髓细胞来抵抗感染而不造成过度的宿主损伤。在这里，我们表明，粒细胞-巨噬细胞集落刺激因子 (GM-CSF) 可以对髓系定型祖细胞进行编程，以产生经过训练的巨噬细胞（细胞因子反应增加），但对上游非定型 LKS 祖细胞（定义为 Lin c-Kit Sca-1 细胞）进行编程产生耐受的巨噬细胞（细胞因子反应降低）。在骨髓祖细胞中，GM-CSF 强烈激活信号转导子和转录激活子 5 (STAT5)、Ras-Raf-细胞外信号调节激酶 (ERK) 和 Akt-mTOR 信号通路，这些信号通路对于建立训练计划至关重要，而在LKS 祖细胞，GM-CSF 诱导 NF-κB 易位至细胞核以建立耐受程序。这些差异是由于与 LKS 细胞相比，骨髓祖细胞中 GM-CSF 受体表达更高。我们证明 NF-κB 核转位的 β-连环蛋白调节是这一过程的核心。在骨髓祖细胞中，强 ERK 和磷脂酰肌醇 3 激酶 (PI3K)-Akt 信号传导导致糖原合酶激酶 3 (GSK3) 失活，从而增加细胞质 β-连环蛋白水平，从而阻断 NF-κB 核转位。相反，当 ERK 和 PI3K-Akt 信号传导较弱时，活跃的 GSK3 会导致 β-catenin 减少，从而允许 LKS 祖细胞中 NF-κB 核易位。最后，GM-CSF 诱导的 LKS 耐受发生在几种经过训练的免疫小鼠模型和人类 CD34 CD38 祖细胞中。我们的研究表明，除了激活骨髓细胞生成外，GM-CSF 还对早期和即刻骨髓祖细胞进行编程，以产生相反的免疫记忆表型。 我们认为，直接骨髓祖细胞的炎症反应可以通过早期祖细胞的耐受表型来平衡，从而提供适当解决炎症和防止长期细胞因子风暴的机制。