title: Macrophage uptake and accumulation of folates are polarization-dependent in vitro and in vivo and are regulated by activin A.
abstract: Vitamin B9, commonly known as folate, is an essential cofactor for one-carbon metabolism that enters cells through three major specialized transporter molecules (RFC, FR, and PCFT), which differ in expression pattern, affinity for substrate, and ligand-binding pH dependency. We now report that the expression of the folate transporters differs between macrophage subtypes and explains the higher accumulation of 5-MTHF-the major folate form found in serum-in M2 macrophages in vitro and in vivo. M1 macrophages display a higher expression of RFC, whereas FRβ and PCFT are preferentially expressed by anti-inflammatory and homeostatic M2 macrophages. These differences are also seen in macrophages from normal tissues involved in folate transit (placenta, liver, colon) and inflamed tissues (ulcerative colitis, RA), as M2-like macrophages from normal tissues express FRβ and PCFT, whereas TNF-α-expressing M1 macrophages from inflamed tissues are RFC+. Besides, we provide evidences that activin A is a critical factor controlling the set of folate transporters in macrophages, as it down-regulates FRβ, up-regulates RFC expression, and modulates 5-MTHF uptake. All of these experiments support the notion that folate handling is dependent on the stage of macrophage polarization.
authors.affiliation: Laboratorio de Inmuno-Metabolismo, Unidad de Microscopía Confocal.
authors.forename: Rafael
authors.initials: R
authors.lastname: Samaniego
authors.affiliation: Laboratorio de Inmuno-Metabolismo, Unidad de Microscopía Confocal.
authors.forename: Blanca Soler
authors.initials: BS
authors.lastname: Palacios
authors.affiliation: Centro de Investigaciones Biológicas, Madrid, Spain.
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Domiguez-Soto
authors.affiliation: Servicio de Traumatología, and.
authors.forename: Carlos
authors.initials: C
authors.lastname: Vidal
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Azucena
authors.initials: A
authors.lastname: Salas
authors.affiliation: Kagoshima University, Kagoshima, Japan.
authors.forename: Takami
authors.initials: T
authors.lastname: Matsuyama
authors.affiliation: Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico Distrito Federal, Mexico; and.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sánchez-Torres
authors.affiliation: Servicio de Reumatología, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: de la Torre
authors.affiliation: Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Miranda-Carús
authors.affiliation: Laboratorio de Inmuno-Metabolismo, Unidad de Microscopía Confocal.
authors.forename: Paloma
authors.initials: P
authors.lastname: Sánchez-Mateos
authors.affiliation: Laboratorio de Inmuno-Metabolismo, Unidad de Microscopía Confocal, amaya.puig@salud.madrid.org.
authors.forename: Amaya
authors.initials: A
authors.lastname: Puig-Kröger
mesh_terms: D028341:Activins / Q000276:immunology*; D016764:Cell Polarity / Q000187:drug effects* / Q000276:immunology; D058976:Folate Receptor 2 / Q000276:immunology*; D005492:Folic Acid / Q000493:pharmacokinetics / Q000494:pharmacology; D058972:Folic Acid Transporters / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000276:immunology*
chemical_list: C000610095:FOLR2 protein, human; D058976:Folate Receptor 2; D058972:Folic Acid Transporters; C422405:activin A; D028341:Activins; D005492:Folic Acid
keywords: folate metabolism; folate receptor beta; folate transporters; macrophage metabolism