title: Atypical Activin A and IL-10 Production Impairs Human CD16+ Monocyte Differentiation into Anti-Inflammatory Macrophages.
abstract: 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 (Mϕ) 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 Mϕs 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 Mϕ 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 Mϕs in a self-autonomous manner, whereas M-CSF-treated CD16(+) monocytes generate Mϕs with a skewed proinflammatory profile by virtue of their high activin A expression unless additional anti-inflammatory stimuli such as IL-10 are provided.
authors.affiliation: Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, 07360 Mexico City, Mexico;
authors.forename: Érika
authors.identifier: http://orcid.org/0000-0001-7404-0038
authors.initials: É
authors.lastname: González-Domínguez
authors.affiliation: Laboratorio de Células Mieloides, Departamento de Microbiología Molecular y Biología de las Infecciones, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, 28040 Madrid, Spain; and.
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Domínguez-Soto
authors.affiliation: Laboratorio de Células Mieloides, Departamento de Microbiología Molecular y Biología de las Infecciones, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, 28040 Madrid, Spain; and.
authors.forename: Concha
authors.initials: C
authors.lastname: Nieto
authors.affiliation: Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, 07360 Mexico City, Mexico;
authors.forename: José Luis
authors.initials: JL
authors.lastname: Flores-Sevilla
authors.affiliation: Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, 07360 Mexico City, Mexico;
authors.forename: Mariana
authors.identifier: http://orcid.org/0000-0003-2930-342X
authors.initials: M
authors.lastname: Pacheco-Blanco
authors.affiliation: Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía "Manuel Velazco Suárez," 14269 Mexico City, Mexico.
authors.forename: Victoria
authors.identifier: http://orcid.org/0000-0001-8282-7543
authors.initials: V
authors.lastname: Campos-Peña
authors.affiliation: Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, 07360 Mexico City, Mexico;
authors.forename: Marco A
authors.identifier: http://orcid.org/0000-0001-6748-8117
authors.initials: MA
authors.lastname: Meraz-Ríos
authors.affiliation: Laboratorio de Células Mieloides, Departamento de Microbiología Molecular y Biología de las Infecciones, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, 28040 Madrid, Spain; and.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Vega
authors.affiliation: Laboratorio de Células Mieloides, Departamento de Microbiología Molecular y Biología de las Infecciones, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, 28040 Madrid, Spain; and.
authors.forename: Ángel L
authors.initials: ÁL
authors.lastname: Corbí
authors.affiliation: Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, 07360 Mexico City, Mexico; csanchez@cinvestav.mx.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sánchez-Torres
mesh_terms: D028341:Activins / Q000096:biosynthesis* / Q000276:immunology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000276:immunology; D008264:Macrophages / Q000166:cytology* / Q000276:immunology; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D017452:Receptors, IgG / Q000276:immunology
chemical_list: C485700:Fcgr3 protein, mouse; C508609:IL10 protein, human; D017452:Receptors, IgG; C422405:activin A; D028341:Activins; D016753:Interleukin-10