Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers

• Published in: Blood 2011-05, Vol.117 (19), p.5092-5101
• Main Authors: Sierra-Filardi, Elena, Puig-Kröger, Amaya, Blanco, Francisco J., Nieto, Concha, Bragado, Rafael, Palomero, M. Isabel, Bernabéu, Carmelo, Vega, Miguel A., Corbí, Angel L.
• Format: Article
• Language: English
• Subjects: Activins - immunology; Activins - metabolism; Animals; Biological and medical sciences; Biomarkers - analysis; Blotting, Western; Cell Differentiation - immunology; Cell Line; Cell Separation; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene Expression - immunology; Gene Expression Profiling; Gene Expression Regulation - immunology; Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Hematologic and hematopoietic diseases; Humans; Inflammation - immunology; Inflammation - metabolism; Macrophage Colony-Stimulating Factor - immunology; Macrophages - cytology; Macrophages - immunology; Macrophages - metabolism; Medical sciences; Mice; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - immunology; Smad Proteins - metabolism; Transfection
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-09-306993

M-CSF favors the generation of folate receptor β–positive (FRβ+), IL-10–producing, immunosuppressive, M2-polarized macrophages [M2 (M-CSF)], whereas GM-CSF promotes a proinflammatory, M1-polarized phenotype [M1 (GM-CSF)]. In the present study, we found that activin A was preferentially released by M1 (GM-CSF) macrophages, impaired the acquisition of FRβ and other M2 (M-CSF)–specific markers, down-modulated the LPS-induced release of IL-10, and mediated the tumor cell growth–inhibitory activity of M1 (GM-CSF) macrophages, in which Smad2/3 is constitutively phosphorylated. The contribution of activin A to M1 (GM-CSF) macrophage polarization was evidenced by the capacity of a blocking anti–activin A antibody to reduce M1 (GM-CSF) polarization markers expression while enhancing FRβ and other M2 (M-CSF) markers mRNA levels. Moreover, an inhibitor of activin receptor-like kinase 4/5/7 (ALK4/5/7 or SB431542) promoted M2 (M-CSF) marker expression but limited the acquisition of M1 (GM-CSF) polarization markers, suggesting a role for Smad2/3 activation in macrophage polarization. In agreement with these results, expression of activin A and M2 (M-CSF)–specific markers was oppositely regulated by tumor ascites. Therefore, activin A contributes to the proinflammatory macrophage polarization triggered by GM-CSF and limits the acquisition of the anti-inflammatory phenotype in a Smad2-dependent manner. Our results demonstrate that activin A–initiated Smad signaling skews macrophage polarization toward the acquisition of a proinflammatory phenotype.