Translation Immunology Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias-ISPA, Oviedo, Spain.
Bioinformatics Unit, CIC bioGUNE, 48160 Derio, Bizkaia, Spain.
Cell Rep. 2019 Oct 22;29(4):860-872.e5. doi: 10.1016/j.celrep.2019.09.035.
In recent years, the macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage CSF (GM-CSF) cytokines have been identified as opposing regulators of the inflammatory program. However, the two cytokines are simultaneously present in the inflammatory milieu, and it is not clear how cells integrate these signals. In order to understand the regulatory networks associated with the GM/M-CSF signaling axis, we analyzed DNA methylation in human monocytes. Our results indicate that GM-CSF induces activation of the inflammatory program and extensive DNA methylation changes, while M-CSF-polarized cells are in a less differentiated state. This inflammatory program is mediated via JAK2 associated with the GM-CSF receptor and the downstream extracellular signal-regulated (ERK) signaling. However, PI3K signaling is associated with a negative regulatory loop of the inflammatory program and M-CSF autocrine signaling in GM-CSF-polarized monocytes. Our findings describe the regulatory networks associated with the GM/M-CSF signaling axis and how they contribute to the establishment of the inflammatory program associated with monocyte activation.
近年来，巨噬细胞集落刺激因子（M-CSF）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）细胞因子已被鉴定为炎症程序的相反调节剂。然而，这两种细胞因子同时存在于炎症环境中，目前尚不清楚细胞如何整合这些信号。为了了解与 GM/M-CSF 信号轴相关的调控网络，我们分析了人单核细胞中的 DNA 甲基化。我们的结果表明，GM-CSF 诱导炎症程序的激活和广泛的 DNA 甲基化变化，而 M-CSF 极化的细胞处于分化程度较低的状态。这个炎症程序是通过与 GM-CSF 受体相关的 JAK2 和下游细胞外信号调节激酶 (ERK) 信号转导介导的。然而，PI3K 信号与炎症程序的负反馈调节环以及 GM-CSF 极化单核细胞中的 M-CSF 自分泌信号有关。我们的研究结果描述了与 GM/M-CSF 信号轴相关的调控网络，以及它们如何有助于建立与单核细胞激活相关的炎症程序。
