Atypical Activin A and IL-10 Production Impairs Human CD16(+) Monocyte Differentiation into Anti- Inflammatory Macrophages

作者：Gonzalez Dominguez Erika; Dominguez Soto Angeles; Nieto Concha; Luis Flores Sevilla Jose; Pacheco Blanco Mariana; Campos Pena Victoria; Meraz Rios Marco A; Vega Miguel A; Corbi Angel L; Sanchez Torres Carmen^*

来源：The Journal of Immunology, 2016, 196(3): 1327-1337.

DOI：10.4049/jimmunol.1501177

Human CD14(++)CD16(-) and CD14(+/lo)CD16(+) monocyte subsets comprise 85 and 15% of blood monocytes, respectively, and are thought to represent distinct stages in the monocyte differentiation pathway. However, the differentiation fates of both monocyte subsets along the macrophage (M phi) lineage have not yet been elucidated. We have now evaluated the potential of CD14(++) CD16(-) and CD16(+) monocytes to differentiate and to be primed toward pro-or anti-inflammatory Mfs upon culture with GM-CSF or M-CSF, respectively (subsequently referred to as GM14, M14, GM16, or M16). Whereas GM16 and GM14 were phenotypic and functionally analogous, M16 displayed a more proinflammatory profile than did M14. Transcriptomic analyses evidenced that genes associated with M-CSF-driven M phi differentiation (including FOLR2, IL10, IGF1, and SERPINB2) are underrepresented in M16 with respect to M14. The preferential proinflammatory skewing of M16 relative to M14 was found to be mediated by the secretion of activin A and the low levels of IL-10 produced by M16. In fact, activin A receptor blockade during the M-CSF-driven differentiation of CD16(+) monocytes, or addition of IL-10-containing M14-conditioned medium, significantly enhanced their expression of anti-inflammatory-associated molecules while impairing their acquisition of proinflammatory-related markers. Thus, we propose that M-CSF drives CD14(++) CD16(-) monocyte differentiation into bona fide anti-inflammatory Mfs in a selfautonomous manner, whereas M-CSF-treated CD16(+) monocytes generate Mfs with a skewed proinflammatory profile by virtue of their high activin A expression unless additional anti-inflammatory stimuli such as IL-10 are provided.

• 出版日期2016-2-1