CCL2 Shapes Macrophage Polarization by GM-CSF and M-CSF: Identification of CCL2/CCR2-Dependent Gene Expression Profile

Journal of Immunology - Tập 192 Số 8 - Trang 3858-3867 - 2014
Elena Sierra‐Filardi1, Concha Nieto1, Ángeles Domínguez‐Soto1, Rubén Barroso2, Paloma Sánchez‐Mateos3, Amaya Puig‐Kröger3, Marı́a López-Bravo2, Jorge Joven4, Carlos Ardavı́n2, José Luis Rodríguez‐Fernández1, Carmen Sánchez‐Torres5, Mario Mellado2, Ángel L. Corbí1
1*Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid 28040, Spain;
2†Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain;
3‡Laboratorio de Inmuno-Metabolismo, Instituto de Investigación Sanitaria Gregorio Marañón, 28007 Madrid, Spain;
4§Unitat de Recerca Biomèdica, Universitat Rovira i Virgili, Reus 43201, Spain; and
5¶Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, 07360 Mexico City, Mexico

Tóm tắt

Abstract The CCL2 chemokine mediates monocyte egress from bone marrow and recruitment into inflamed tissues through interaction with the CCR2 chemokine receptor, and its expression is upregulated by proinflammatory cytokines. Analysis of the gene expression profile in GM-CSF– and M-CSF–polarized macrophages revealed that a high CCL2 expression characterizes macrophages generated under the influence of M-CSF, whereas CCR2 is expressed only by GM-CSF–polarized macrophages. Analysis of the factors responsible for this differential expression identified activin A as a critical factor controlling the expression of the CCL2/CCR2 pair in macrophages, as activin A increased CCR2 expression but inhibited the acquisition of CCL2 expression by M-CSF–polarized macrophages. CCL2 and CCR2 were found to determine the extent of macrophage polarization because CCL2 enhances the LPS-induced production of IL-10, whereas CCL2 blockade leads to enhanced expression of M1 polarization-associated genes and cytokines, and diminished expression of M2-associated markers in human macrophages. Along the same line, Ccr2-deficient bone marrow–derived murine macrophages displayed an M1-skewed polarization profile at the transcriptomic level and exhibited a significantly higher expression of proinflammatory cytokines (TNF-α, IL-6) in response to LPS. Therefore, the CCL2-CCR2 axis regulates macrophage polarization by influencing the expression of functionally relevant and polarization-associated genes and downmodulating proinflammatory cytokine production.

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Journal of Immunology

Tập 192 Số 8

3858-3867

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