title: CCL2 shapes macrophage polarization by GM-CSF and M-CSF: identification of CCL2/CCR2-dependent gene expression profile.
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.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid 28040, Spain;
authors.forename: Elena
authors.initials: E
authors.lastname: Sierra-Filardi
authors.forename: Concha
authors.initials: C
authors.lastname: Nieto
authors.forename: Angeles
authors.initials: A
authors.lastname: Domínguez-Soto
authors.forename: Rubén
authors.initials: R
authors.lastname: Barroso
authors.forename: Paloma
authors.initials: P
authors.lastname: Sánchez-Mateos
authors.forename: Amaya
authors.initials: A
authors.lastname: Puig-Kroger
authors.forename: María
authors.initials: M
authors.lastname: López-Bravo
authors.forename: Jorge
authors.initials: J
authors.lastname: Joven
authors.forename: Carlos
authors.initials: C
authors.lastname: Ardavín
authors.forename: José L
authors.initials: JL
authors.lastname: Rodríguez-Fernández
authors.forename: Carmen
authors.initials: C
authors.lastname: Sánchez-Torres
authors.forename: Mario
authors.initials: M
authors.lastname: Mellado
authors.forename: Angel L
authors.initials: AL
authors.lastname: Corbí
mesh_terms: D028341:Activins / Q000494:pharmacology; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D054412:Chemokine CCL8 / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D018932:Chemokine CCL2; D054412:Chemokine CCL8; D008070:Lipopolysaccharides; D054390:Receptors, CCR2; C422405:activin A; D028341:Activins; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor