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.

Downregulation of Inflammatory MicroRNAs by Ig-like Transcript 3 Is Essential for the Differentiation of Human CD8+ T Suppressor Cells

“…Because exosomes can affect immune cells if they deliver a specific mRNA or miRNA that can modify gene expression in a recipient cell (46,47), it may become possible to deliver Ts signature genes or inhibitors of miR-21, -155, and -30b alone or in combination to generate CD8 + Ts. Alternatively, immune deficiencies may be treated by interfering with the generation and function of Ts, inhibiting their signature genes by targeted delivery of miRNA or by blockade of the ILT3 interaction with its T cell ligand.…”

microRNAs function in CD8+T cell biology

“…Lastly, 2 studies in mice have confirmed an importance of miR-21 in autoimmune T cell responses. The overexpression of miR-21 in T cells causes autoimmune cholangitis in vivo, whereas inhibition of miR-21 in T cells reverses cardinal manifestations of autoimmunity in lupus-prone mice [76,77]. These activities are linked to the ability of miR-21 to repress PDCD4, a selective protein translation inhibitor of genes involved in effector T cell survival and function [78,79].…”

“…The roles of miRNAs are only beginning to be explored in CD8 + T cell-related autoimmune diseases, in which they may be involved in regulating immune responses against self-tissues. Studies in mice showed that the overexpression of miR-21 in T cells potentiates disease severity in the context of experimental autoimmune cholangitis [77], whereas inhibition of miR-21 in T cells attenuates disease severity in the setting of experimental autoimmune lupus [76]. Table 1 indicates the role of candidate miRNAs in various CD8 + T cellrelated diseases.…”

Inhibition of matrix metalloproteinases 9 and 13 affects the degree of lymphocytic infiltration and the expression levels of microRNA miR-21 and miR-let-7b in melanoma cells in vivo

“…TGF-β-путь как один из ре-гуляторов иммунного ответа является основным сигналь-ным путем, способным сдерживать CD4 + T-лимфоциты в состоянии покоя [15]. В реализации данного механизма принимает участие miR-21, ингибирование которой in vivo при системной красной волчанке способствует усиле-нию экспрессии генов, отвечающих за созревание и функ-циональную активность Т-и NK-клеток [16]. При этом TGF-β обеспечивает конвертацию pri-miR-21 в premiR-21 [17].…”