title: miR-146a is differentially expressed by myeloid dendritic cell subsets and desensitizes cells to TLR2-dependent activation.
abstract: Langerhans cells (LCs) in epithelia and interstitial dendritic cells (intDCs) in adjacent connective tissues represent two closely related myeloid-derived DC subsets that exert specialized functions in the immune system and are of clinical relevance for cell therapy. Both subsets arise from monocyte-committed intermediates in response to tissue-associated microenvironmental signals; however, molecular mechanisms underlying myeloid DC subset specification and function remain poorly defined. Using microarray profiling, we identified microRNA (miRNA) miR-146a to be constitutively expressed at higher levels in human LCs compared with intDCs. Moreover, miR-146a levels were low in monocytes and nondetectable in neutrophil granulocytes. Interestingly, constitutive high miR-146a expression in LCs is induced by the transcription factor PU.1 in response to TGF-beta1, a key microenvironmental signal for epidermal LC differentiation. We identified miR-146a as a regulator of monocyte and DC activation but not myeloid/DC subset differentiation. Ectopic miR-146a in monocytes and intDCs interfered with TLR2 downstream signaling and cytokine production, without affecting phenotypic DC maturation. Inversely, silencing of miR-146a in LCs enhanced TLR2-dependent NF-kappaB signaling. We therefore conclude that high constitutive miR-146a levels are induced by microenvironmental signals in the epidermis and might render LCs less susceptible to inappropriate activation by commensal bacterial TLR2 triggers at body surfaces.
authors.affiliation: Center of Physiology, Pathophysiology and Immunology, Institute of Immunology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jurkin
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Schichl
authors.forename: Rene
authors.initials: R
authors.lastname: Koeffel
authors.forename: Thomas
authors.initials: T
authors.lastname: Bauer
authors.forename: Susanne
authors.initials: S
authors.lastname: Richter
authors.forename: Sabine
authors.initials: S
authors.lastname: Konradi
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gesslbauer
authors.forename: Herbert
authors.initials: H
authors.lastname: Strobl
mesh_terms: D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D003888:Desensitization, Immunologic / Q000379:methods; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004817:Epidermis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000502:physiology; D020298:U937 Cells; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D051195:Toll-Like Receptor 2; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1; D000099232:Proto-Oncogene Protein Spi-1; C542542:MIRN146 microRNA, human; C508960:TGFB1 protein, human; C495342:TLR2 protein, human