151. Signal Integration and Transcriptional Regulation of the Inflammatory Response Mediated by the GM-/M-CSF Signaling Axis in Human Monocytes
- Author
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Juan José Lozano, Ana M. Aransay, Aroa Baragaño Raneros, Marcos J. Araúzo-Bravo, José Luis Lavín, Carlos López-Larrea, Beatriz Suarez-Alvarez, Marta Ruiz-Ortega, Covadonga Huidobro, Ana Belen Sanz, Ramon M. Rodriguez, Angel L. Corbí, Paula Díaz Bulnes, Jose Ramón Vidal-Castiñeira, Cristina Martin-Martin, Amaya Puig-Kröger, Monika González, Alex M. Ascensión, UAM. Departamento de Medicina, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Instituto de Salud Carlos III, Principado de Asturias, European Commission, Red Española de Investigación Renal, Ministerio de Economía y Competitividad (España), Rodríguez, Ramón M, Lavín, José L., Ascensión, Alex M., Lozano, Juan José, Raneros, Aroa B., Vidal-Castiñeira, José Ramón, Huidobro, Covadonga, Ruiz-Ortega, Marta, Puig-Kröger, Amaya, Corbí, Angel L., Araúzo-Bravo, Marcos J., Aransay, Ana M., López-Larrea, Carlos, Rodríguez, Ramón M [0000-0002-6770-5123], Lavín, José L. [0000-0003-0914-3211], Ascensión, Alex M. [0000-0002-0013-3052], Lozano, Juan José [0000-0001-7613-3908], Raneros, Aroa B. [0000-0002-8264-0276], Vidal-Castiñeira, José Ramón [0000-0003-4877-3566], Huidobro, Covadonga [0000-0001-9823-3846], Ruiz-Ortega, Marta [0000-0002-1495-6535], Puig-Kröger, Amaya [0000-0003-2943-9757], Corbí, Angel L.[0000-0003-1980-5733], Araúzo-Bravo, Marcos J. [0000-0002-3264-464X], Aransay, Ana M. [0000-0002-0013-3052], and López-Larrea, Carlos [0000-0001-9988-1730]
- Subjects
Adult ,0301 basic medicine ,MAPK/ERK pathway ,Plasticity ,Macrophage ,Medicina ,Biology ,Gm-Csf ,Monocyte ,Monocytes ,General Biochemistry, Genetics and Molecular Biology ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,Polarization ,medicine ,Transcriptional regulation ,Humans ,Epigenetics ,Autocrine signalling ,Receptor ,lcsh:QH301-705.5 ,Cells, Cultured ,Inflammation ,Mitogen-Activated Protein Kinase 1 ,Mitogen-Activated Protein Kinase 3 ,Macrophage Colony-Stimulating Factor ,Granulocyte-Macrophage Colony-Stimulating Factor ,Janus Kinase 2 ,DNA Methylation ,M-Csf ,Chromatin ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Biology (General) ,Differentiation ,DNA methylation ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
19 p.-6 fig., 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., This work was supported by grants from the Plan Nacional de I+D+I 2013– 2016 ISCIII (Institute of Health Carlos III; PI16/01318, PI17/01244, PI17/ 0119, PI16/1900, and PI19/00184); the Gobierno del Principado de Asturias; the PCTI-Plan de Ciencia, Tecnología e Innovación 2013-2017 (grant IDI/ 2018/144); FEDER ‘‘Funding Program of the European Union’’; the Red Española de Investigación Renal (REDinREN) (RD16/0009/0020, RD016/0009/002, and RD016/0009/001); the Agencia Estatal de Investigación (AEI) (ayuda Juan de la Cierva-Incorporaciόn; IJCI-2017-33347 to R.M.R.); and the Instituto de Salud Carlos III (Contratos Sara Borrell; CD16/00033 to C.H.). CIC bioGUNE support was provided by the Basque Department of Industry, Tourism and Trade (Etortek and Elkartek programs), the Innovation Technology Department of Bizkaia County, the CIBERehd Network, and Spanish MINECO, the Severo Ochoa Excellence Accreditation (SEV-2016-0644).
- Published
- 2019