title: Activin A induces Langerhans cell differentiation in vitro and in human skin explants.
abstract: Langerhans cells (LC) represent a well characterized subset of dendritic cells located in the epidermis of skin and mucosae. In vivo, they originate from resident and blood-borne precursors in the presence of keratinocyte-derived TGFbeta. In vitro, LC can be generated from monocytes in the presence of GM-CSF, IL-4 and TGFbeta. However, the signals that induce LC during an inflammatory reaction are not fully investigated. Here we report that Activin A, a TGFbeta family member induced by pro-inflammatory cytokines and involved in skin morphogenesis and wound healing, induces the differentiation of human monocytes into LC in the absence of TGFbeta. Activin A-induced LC are Langerin+, Birbeck granules+, E-cadherin+, CLA+ and CCR6+ and possess typical APC functions. In human skin explants, intradermal injection of Activin A increased the number of CD1a+ and Langerin+ cells in both the epidermis and dermis by promoting the differentiation of resident precursor cells. High levels of Activin A were present in the upper epidermal layers and in the dermis of Lichen Planus biopsies in association with a marked infiltration of CD1a+ and Langerin+ cells. This study reports that Activin A induces the differentiation of circulating CD14+ cells into LC. Since Activin A is abundantly produced during inflammatory conditions which are also characterized by increased numbers of LC, we propose that this cytokine represents a new pathway, alternative to TGFbeta, responsible for LC differentiation during inflammatory/autoimmune conditions.
authors.affiliation: Department of Public Health and Microbiology, University of Torino, Turin, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Musso
authors.forename: Sara
authors.initials: S
authors.lastname: Scutera
authors.forename: William
authors.initials: W
authors.lastname: Vermi
authors.forename: Roberta
authors.initials: R
authors.lastname: Daniele
authors.forename: Michele
authors.initials: M
authors.lastname: Fornaro
authors.forename: Carlotta
authors.initials: C
authors.lastname: Castagnoli
authors.forename: Daniela
authors.initials: D
authors.lastname: Alotto
authors.forename: Maria
authors.initials: M
authors.lastname: Ravanini
authors.forename: Irene
authors.initials: I
authors.lastname: Cambieri
authors.forename: Laura
authors.initials: L
authors.lastname: Salogni
authors.forename: Angela Rita
authors.initials: AR
authors.lastname: Elia
authors.forename: Mirella
authors.initials: M
authors.lastname: Giovarelli
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.forename: Giampiero
authors.initials: G
authors.lastname: Girolomoni
authors.forename: Silvano
authors.initials: S
authors.lastname: Sozzani
mesh_terms: D028341:Activins / Q000378:metabolism*; D015703:Antigens, CD / Q000096:biosynthesis; D018949:Antigens, CD1 / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000166:cytology; D007801:Langerhans Cells / Q000166:cytology*; D037181:Lectins, C-Type / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D037241:Mannose-Binding Lectins / Q000096:biosynthesis; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014945:Wound Healing
chemical_list: D015703:Antigens, CD; D018949:Antigens, CD1; C419393:CD1a antigen; C121916:CD207 protein, human; D037181:Lectins, C-Type; D018950:Lipopolysaccharide Receptors; D037241:Mannose-Binding Lectins; D016212:Transforming Growth Factor beta; C422405:activin A; D028341:Activins