title: The Complement Inhibitor Factor H Generates an Anti-Inflammatory and Tolerogenic State in Monocyte-Derived Dendritic Cells.
abstract: The activation of the complement system is a key initiating step in the protective innate immune-inflammatory response against injury, although it may also cause harm if left unchecked. The structurally related soluble complement inhibitors C4b-binding protein (C4BP) and factor H (FH) exert a tight regulation of the classical/lectin and alternative pathways of complement activation, respectively, attenuating the activity of the C3/C5 convertases and, consequently, avoiding serious damage to host tissues. We recently reported that the acute-phase C4BP isoform C4BP lacking the β-chain plays a pivotal role in the modulation of the adaptive immune responses. In this study, we demonstrate that FH acts in the early stages of monocyte to dendritic cell (DC) differentiation and is able to promote a distinctive tolerogenic and anti-inflammatory profile on monocyte-derived DCs (MoDCs) challenged by a proinflammatory stimulus. Accordingly, FH-treated and LPS-matured MoDCs are characterized by altered cytoarchitecture, resembling immature MoDCs, lower expression of the maturation marker CD83 and the costimulatory molecules CD40, CD80, and CD86, decreased production of key proinflammatory Th1-cytokines (IL-12, TNF-α, IFN-γ, IL-6, and IL-8), and preferential production of immunomodulatory mediators (IL-10 and TGF-β). Moreover, FH-treated MoDCs show low Ag uptake and, when challenged with LPS, display reduced CCR7 expression and chemotactic migration, impaired CD4(+) T cell alloproliferation, inhibition of IFN-γ secretion by the allostimulated T cells, and, conversely, induction of CD4(+)CD127(low/negative)CD25(high)Foxp3(+) regulatory T cells. Thus, this novel noncanonical role of FH as an immunological brake able to directly affect the function of MoDCs in an inflammatory environment may exhibit therapeutic potential in hypersensitivity, transplantation, and autoimmunity.
authors.affiliation: Human Molecular Genetics Group, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, 08908 Barcelona, Spain;
authors.forename: Rut
authors.initials: R
authors.lastname: Olivar
authors.affiliation: Human Molecular Genetics Group, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, 08908 Barcelona, Spain;
authors.forename: Ana
authors.initials: A
authors.lastname: Luque
authors.affiliation: Human Molecular Genetics Group, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, 08908 Barcelona, Spain;
authors.forename: Sonia
authors.initials: S
authors.lastname: Cárdenas-Brito
authors.affiliation: Innovation in Vesicles and Cells for Application Therapy Group, Germans Trias i Pujol Health Sciences Research Institute, 08916 Badalona, Barcelona, Spain; Nephrology Service, Germans Trias i Pujol University Hospital, 08916 Badalona, Barcelona, Spain;
authors.forename: Mar
authors.identifier: 0000-0002-7068-2671
authors.initials: M
authors.lastname: Naranjo-Gómez
authors.affiliation: Section of Medical Protein Chemistry, Department of Laboratory Medicine, Lund University, 20502 Malmö, Sweden;
authors.forename: Anna M
authors.identifier: 0000-0002-1348-1734
authors.initials: AM
authors.lastname: Blom
authors.affiliation: Innovation in Vesicles and Cells for Application Therapy Group, Germans Trias i Pujol Health Sciences Research Institute, 08916 Badalona, Barcelona, Spain; Nephrology Service, Germans Trias i Pujol University Hospital, 08916 Badalona, Barcelona, Spain;
authors.forename: Francesc E
authors.identifier: 0000-0003-4038-1912
authors.initials: FE
authors.lastname: Borràs
authors.affiliation: Centro de Investigaciones Biológicas, 28040 Madrid, Spain; Ciber de Enfermedades Raras, 28040 Madrid, Spain; and.
authors.forename: Santiago
authors.identifier: 0000-0001-6401-1874
authors.initials: S
authors.lastname: Rodriguez de Córdoba
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Products Research and Infection Biology, 07745 Jena, Germany.
authors.forename: Peter F
authors.identifier: 0000-0002-6149-2411
authors.initials: PF
authors.lastname: Zipfel
authors.affiliation: Human Molecular Genetics Group, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, 08908 Barcelona, Spain; jaran@idibell.cat.
authors.forename: Josep M
authors.identifier: 0000-0003-2827-9392
authors.initials: JM
authors.lastname: Aran
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002633:Chemotaxis; D050716:Complement C4b-Binding Protein / Q000276:immunology; D017242:Complement Factor H / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004705:Endocytosis; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D015703:Antigens, CD; C493495:CFH protein, human; D050716:Complement C4b-Binding Protein; D016207:Cytokines; D017242:Complement Factor H