Signal integration and transcriptional regulation of the inflammatory response mediated by the GM-/MCSF signaling axis in human monocytes

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...

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Bibliographic Details
Authors: Rodríguez, Ramón M., Suárez-Álvarez, Beatriz, Lavín, José L., Ascensión, Alex M., González, Monika, Lozano, Juan J., Raneros, Aroa B., Bulnes, Paula D., Vidal-Castiñeira, Jose R., Huidobro, Covadonga, Martín-Martín, Cristina, Sanz, Ana Belén, Ruiz Ortega, Marta, Puig-Kröger, Amaya, Corbi, Ángel L., Araúzo-Bravo, Marcos J., Aransay, Ana M., López-Larrea, Carlos
Format: article
Publication Date:2019
Country:España
Institution:Universidad Autónoma de Madrid
Repository:Biblos-e Archivo. Repositorio Institucional de la UAM
Language:English
OAI Identifier:oai:repositorio.uam.es:10486/691281
Online Access:http://hdl.handle.net/10486/691281
https://dx.doi.org/10.1016/j.celrep.2019.09.035
Access Level:Open access
Keyword:Epigenetics
Gm-Csf
M-Csf
DNA Methylation
Chromatin
Monocyte
Macrophage
Differentiation
Plasticity
Polarization
Medicina
Description
Summary: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.

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