Silencing of microRNA‐21 in vivo ameliorates autoimmune splenomegaly in lupus mice

• Published in: EMBO molecular medicine 2011-10, Vol.3 (10), p.605-615
• Main Authors: Garchow, Barry G., Bartulos Encinas, Oscar, Leung, Yiu Tak, Tsao, Patricia Y., Eisenberg, Robert A., Caricchio, Roberto, Obad, Susanna, Petri, Andreas, Kauppinen, Sakari, Kiriakidou, Marianthi
• Format: Article
• Language: English
• Subjects: Age; Aging - drug effects; Aging - pathology; Animals; Apoptosis; Apoptosis Regulatory Proteins - metabolism; Autoantibodies; Autoimmune diseases; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Autoimmunity; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; CD4 antigen; CD4-CD8 Ratio; CD8 antigen; Cell differentiation; Cell growth; Cell lineage; fas Receptor - metabolism; Flow cytometry; Gene expression; Gene Expression Profiling; Gene Expression Regulation - drug effects; Gene Silencing - drug effects; Glomerulonephritis; Interferon; Kidney diseases; Lupus; Lupus Erythematosus, Systemic - complications; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lymphocyte Subsets - drug effects; Lymphocyte Subsets - immunology; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - metabolism; Lymphocytes B; Lymphocytes T; Mice; Mice, Inbred C57BL; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; miR‐21/PDCD4; Oligonucleotides - pharmacology; Pathogenesis; Population studies; Research Article; RNA-Binding Proteins - metabolism; SLE; Splenomegaly; Splenomegaly - complications; Splenomegaly - genetics; Splenomegaly - immunology; Splenomegaly - pathology; Statistical analysis; Studies; Systemic lupus erythematosus; T cell receptors; Transcription, Genetic - drug effects
• ISSN: 1757-4676; 1757-4684
• DOI: 10.1002/emmm.201100171

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.