Sierra-Filardi, Elena;
Puig-Kröger, Amaya;
Blanco, Francisco J.;
Nieto, Concha;
Bragado, Rafael;
Palomero, M. Isabel;
Bernabéu, Carmelo;
Vega, Miguel A.;
Corbí, Angel L.
Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers
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Media type:
E-Article
Title:
Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers
Contributor:
Sierra-Filardi, Elena;
Puig-Kröger, Amaya;
Blanco, Francisco J.;
Nieto, Concha;
Bragado, Rafael;
Palomero, M. Isabel;
Bernabéu, Carmelo;
Vega, Miguel A.;
Corbí, Angel L.
imprint:
American Society of Hematology, 2011
Published in:Blood
Language:
English
DOI:
10.1182/blood-2010-09-306993
ISSN:
0006-4971;
1528-0020
Origination:
Footnote:
Description:
<jats:title>Abstract</jats:title><jats:p>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.</jats:p>