Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory
Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers
Sierra-Filardi, et al. Blood 117: 5092-5101, 2011.
Speaker: Chao-Ho Li (李兆和) Date: 13:00-14:00 May. 9, 2012
Commentator: Dr. Chih-Peng Chang (張志鵬老師) Place: Classroom 601
Abstract:
Macrophage plays an important role in many immunological responses especially in tumorigenesis, inflammation, and would healing. Based on its phenotype, macrophage can be divided into classical macrophage (M1, proinflammatory) and alternative macrophage (M2, anti-inflammatory and tissue remodeling.) M-CSF (macrophage colony-stimulating factor) and GM-CSF (granulocyte-macrophage colony-stimulating factor) are important for cell survival and proliferation, but they have distinctive roles in macrophage polarization. M1 and M2 can be generated in the presence of GM-SCF and M-SCF, respectively. Activin A is a pluripotent growth factor of TGF-β superfamily, which can be secreted by leukocytes, and it regulates cell proliferation, fibrosis, and hematopoiesis. Previous study has shown that the expression level of activin A is high in patients with rheumatoid arthritis or inflammatory bowel disease.1 In this study, the authors found that activin A could be secreted by M1 macrophages and hindered the M2 polarization in the marker or cytokine profile.2 Cultured monocytes treated with GM-CSF-free M1 macrophage-conditioned medium or anti-activin A antibody showed higher M2 gene expression levels, indicating that activin A indeed influences macrophage polarization. Moreover, activin A can also arrest cancer cell growth cycle. GM-CSF-free M1 macrophage-conditioned medium or activin A could significantly inhibit K562 leukemia cell growth, which was significantly reverted in the presence of anti-activin A or SB431542 (an ALK4/5/7 inhibitor known to prevent Smad2/3 signaling). The authors also discovered that Smad2 was constitutively phosphorylated in M1 but not M2 macrophages, and the presence of anti-activin A or SB431542 could prevent Smad2 phosphorylation. To sum up, activin A prefers M1 polarization via Smad2/3 activation and inflammatory cytokine secretion for preventing tumor cell proliferation. This study provides novel potential therapeutic targets for modulating macrophage inflammatory response under pathologic conditions.
References
1. Yu, J., Shao, L.E., Frigon, N.L., Jr., Lofgren, J., & Schwall, R., Induced expression of the new cytokine, activin A, in human monocytes: inhibition by glucocorticoids and retinoic acid. Immunology 88: 368-374, 1996.
2. Martinez, F.O., Gordon, S., Locati, M., & Mantovani, A., Transcriptional Profiling of the Human Monocyte-to-Macrophage Differentiation and Polarization: New Molecules and Patterns of Gene Expression. J. Immunol. 177: 7303-7311, 2006.