title: MicroRNA-29b modulates innate and antigen-specific immune responses in mouse models of autoimmunity.
abstract: In addition to important regulatory roles in gene expression through RNA interference, it has recently been shown that microRNAs display immune stimulatory effects through direct interaction with receptors of innate immunity of the Toll-like receptor family, aggravating neuronal damage and tumour growth. Yet no evidence exists on consequences of microRNA immune stimulatory actions in the context of an autoimmune disease. Using microRNA analogues, we here show that pancreatic beta cell-derived microRNA sequences induce pro-inflammatory (TNFa, IFNa, IL-12, IL-6) or suppressive (IL-10) cytokine secretion by primary mouse dendritic cells in a sequence-dependent manner. For miR-29b, immune stimulation in RAW264.7 macrophages involved the endosomal Toll-like receptor-7, independently of the canonical RNA interference pathway. In vivo, the systemic delivery of miR-29b activates CD11b+B220- myeloid and CD11b-B220+ plasmacytoid dendritic cells and induces IFNa, TNFa and IL-6 production in the serum of recipient mice. Strikingly, in a murine model of adoptive transfer of autoimmune diabetes, miR-29b reduces the cytolytic activity of transferred effector CD8+ T-cells, insulitis and disease incidence in a single standalone intervention. Endogenous miR-29b, spontaneously released from beta-cells within exosomes, stimulates TNFa secretion from spleen cells isolated from diabetes-prone NOD mice in vitro. Hence, microRNA sequences modulate innate and ongoing adaptive immune responses raising the question of their potential role in the breakdown of tolerance and opening up new applications for microRNA-based immune therapy.
authors.affiliation: LUNAM Université, Oniris, EA 4644 IECM, Nantes, France; INRA, Nantes, France.
authors.forename: Apolline
authors.initials: A
authors.lastname: Salama
authors.affiliation: LUNAM Université, Oniris, EA 4644 IECM, Nantes, France; INRA, Nantes, France.
authors.forename: Nolwenn
authors.initials: N
authors.lastname: Fichou
authors.affiliation: LUNAM Université, Oniris, EA 4644 IECM, Nantes, France; INRA, Nantes, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Allard
authors.affiliation: INRA, Nantes, France; LUNAM Université, Oniris, UMR_A0703 PanTHER, Nantes, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Dubreil
authors.affiliation: LUNAM Université, Oniris, EA 4644 IECM, Nantes, France; INRA, Nantes, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: De Beaurepaire
authors.affiliation: LUNAM Université, Oniris, EA 4644 IECM, Nantes, France; INRA, Nantes, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Viel
authors.affiliation: LUNAM Université, Oniris, EA 4644 IECM, Nantes, France; INRA, Nantes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Jégou
authors.affiliation: LUNAM Université, Oniris, EA 4644 IECM, Nantes, France; INRA, Nantes, France.
authors.forename: Steffi
authors.initials: S
authors.lastname: Bösch
authors.affiliation: LUNAM Université, Oniris, EA 4644 IECM, Nantes, France; INRA, Nantes, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Bach
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D000941:Antigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D011992:Endosomes / Q000378:metabolism; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000378:metabolism
chemical_list: D000941:Antigens; D016207:Cytokines; C547014:MIRN29 microRNA, mouse; D008562:Membrane Glycoproteins; D035683:MicroRNAs; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7