title: Silencing of microRNA-21 in vivo ameliorates autoimmune splenomegaly in lupus mice.
abstract: MicroRNAs (miRNAs) have been implicated in B cell lineage commitment, regulation of T cell differentiation, TCR signalling, regulation of IFN signalling, and numerous other immunological processes. However, their function in autoimmunity, and specifically in systemic lupus erythematosus (SLE), remains poorly understood. B6.Sle123 is a spontaneous genetic mouse model of SLE characterized by autoantibody production, lymphosplenomegaly, and glomerulonephritis. We identified several differentially regulated miRNAs in B and T lymphocytes of B6.Sle123 mice. We found that miR-21 expression in lupus B and T cells is up-regulated and that in vivo silencing of miR-21 using a tiny seed-targeting LNA reversed splenomegaly, one of the cardinal manifestations of autoimmunity in B6.Sle123 mice, and de-repressed PDCD4 expression in vivo and in vitro. In addition, treatment with anti-miR-21 altered CD4/CD8 T cell ratios and reduced Fas receptor-expressing lymphocyte populations. Our study shows that tiny LNAs can be used to efficiently antagonize endogenous miRNAs in peripheral lymphocytes in vivo and in primary lymphocytes cultured ex vivo and can alter the course of a spontaneous genetic disease in mice.
authors: Division of Rheumatology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, USA.
authors: Barry G
authors: BG
authors: Garchow
authors: Oscar
authors: O
authors: Bartulos Encinas
authors: Yiu Tak
authors: YT
authors: Leung
authors: Patricia Y
authors: PY
authors: Tsao
authors: Robert A
authors: RA
authors: Eisenberg
authors: Roberto
authors: R
authors: Caricchio
authors: Susanna
authors: S
authors: Obad
authors: Andreas
authors: A
authors: Petri
authors: Sakari
authors: S
authors: Kauppinen
authors: Marianthi
authors: M
authors: Kiriakidou
mesh_terms: D000375:Aging / Q000187:drug effects / Q000473:pathology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016516:CD4-CD8 Ratio; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000235:genetics* / Q000276:immunology; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism; D013163:Splenomegaly / Q000150:complications / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D009841:Oligonucleotides; C498443:Pdcd4 protein, mouse; D016601:RNA-Binding Proteins; D019014:fas Receptor; C477371:locked nucleic acid