title: MicroRNA-146a regulates survival and maturation of human plasmacytoid dendritic cells.
abstract: During microbial infections, plasmacytoid dendritic cells (pDCs) are a main source of type I interferons α/β (IFN-α/-β). Nucleic acids from microbes are sensed by Toll-like receptors 7/9 (TLR7/9), which are selectively expressed in pDCs. Activated pDCs also produce proinflammatory cytokines and upregulate costimulatory molecules. Together, this equips pDCs with the ability to prime T, B, and NK cells and conventional DCs, thereby initiating adaptive immune responses. To avoid deleterious effects to the host, tight regulation of pDC activation is required. Despite data linking aberrant activation of pDCs with autoimmune diseases, little is known about mechanisms controlling pDC activation. Here, we investigated the role of microRNA-146a (miR-146a) in TLR pathway regulation in human pDCs. MiR-146a expression was induced upon TLR7/9 signaling. Furthermore, ectopic miR-146a expression effectively impaired TLR-mediated signaling in pDCs as TLR-induced nuclear factor-κB activation was reduced. This consequently diminished the production of proinflammatory cytokines and reduced pDC survival. Moreover, miR-146a-expressing pDCs had decreased ability to induce CD4(+) T-cell proliferation likely due to reduced expression levels of major histocompatibility complex class II and costimulatory molecules. Our data unravel the crucial immunomodulatory role of miR-146a in pDCs and may add to our understanding of aberrant responses in autoimmune diseases.
authors.affiliation: Department of Cell Biology and Histology and.
authors.forename: Julien J
authors.initials: JJ
authors.lastname: Karrich
authors.forename: Loes C M
authors.initials: LC
authors.lastname: Jachimowski
authors.forename: Marion
authors.initials: M
authors.lastname: Libouban
authors.forename: Anand
authors.initials: A
authors.lastname: Iyer
authors.forename: Kim
authors.initials: K
authors.lastname: Brandwijk
authors.forename: Esther W
authors.initials: EW
authors.lastname: Taanman-Kueter
authors.forename: Maho
authors.initials: M
authors.lastname: Nagasawa
authors.forename: Esther C
authors.initials: EC
authors.lastname: de Jong
authors.forename: Christel H
authors.initials: CH
authors.lastname: Uittenbogaart
authors.forename: Bianca
authors.initials: B
authors.lastname: Blom
mesh_terms: D056704:Adaptive Immunity; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002675:Child, Preschool; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D007223:Infant; D008213:Lymphocyte Activation; D035683:MicroRNAs / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology
chemical_list: D000949:Histocompatibility Antigens Class II; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9