UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology

Date

1-1-2015

Document Type

Article

Subjects

Adjuvants, Immunologic; Animals; Base Sequence; HEK293 Cells; Humans; Mice; MicroRNAs; Nucleotide Motifs; Oligonucleotides; RNA; Toll-Like Receptor 7; Toll-Like Receptor 8

Disciplines

Biochemistry | Immunology and Infectious Disease | Nucleic Acids, Nucleotides, and Nucleosides

Abstract

Anti-microRNA (miRNA) oligonucleotides (AMOs) with 2'-O-Methyl (2'OMe) residues are commonly used to study miRNA function and can achieve high potency, with low cytotoxicity. Not withstanding this, we demonstrate the sequence-dependent capacity of 2'OMe AMOs to inhibit Toll-like receptor (TLR) 7 and 8 sensing of immunostimulatory RNA, independent of their miRNA-targeting function. Through a screen of 29 AMOs targeting common miRNAs, we found a subset of sequences highly inhibitory to TLR7 sensing in mouse macrophages. Interspecies conservation of this inhibitory activity was confirmed on TLR7/8 activity in human peripheral blood mononuclear cells. Significantly, we identified a core motif governing the inhibitory activity of these AMOs, which is present in more than 50 AMOs targeted to human miRNAs in miRBaseV20. DNA/locked nucleic acids (LNA) AMOs synthesized with a phosphorothioate backbone also inhibited TLR7 sensing in a sequence-dependent manner, demonstrating that the off-target effects of AMOs are not restricted to 2'OMe modification. Taken together, our work establishes the potential for off-target effects of AMOs on TLR7/8 function, which should be taken into account in their therapeutic development and in vivo application.

Rights and Permissions

Citation: Nucleic Acids Res. 2015 Jan;43(2):1177-88. doi: 10.1093/nar/gku1343. Epub 2014 Dec 24. Link to article on publisher's site.

DOI of Published Version

10.1093/nar/gku1343

Comments

© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Related Resources

Link to Article in PubMed

Journal Title

Nucleic acids research

PubMed ID

25539920

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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