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

Abstract

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.

The Prolyl Hydroxylase PHD3 Identifies Proinflammatory Macrophages and Its Expression Is Regulated by Activin A

“…1F). The M1(GM-CSF) macrophage-restricted expression of PHD3 was further evidenced upon costaining with an mAb specific for the FRb, for which expression is only found in M2(M-CSF) macrophages (29). As shown in Fig.…”

Role of Integrin-β3 Protein in Macrophage Polarization and Regeneration of Injured Muscle

“…Furthermore, proinflammatory M1 macrophages in injured muscles have been reported to be converted into an M2 phenotype (21). Conversely, activin A (a member of TGF-␤ superfamily) promotes an increase in the proinflammatory M1 phenotype but inhibits M2 macrophages (24).…”

The bright and the dark sides of activin in wound healing and cancer

“…However, a recent study on human macrophages demonstrated the opposite effect; activin was preferentially released by M1 macrophages and contributed to M1 polarization (Sierra-Filardi et al, 2011). As macrophages represent a dynamic cell population and are able to repolarize under the appropriate cytokine conditions (Gratchev et al, 2006), it has been suggested that activin acts as a switch between these polarization states (Sierra-Filardi et al, 2011).…”