Sequence-dependent off-target inhibition of TLR7/8 sensing by synthetic microRNA inhibitors

Soroush Sarvestani, Hilary James Stunden, Mark A Behlke, Samuel Forster, Claire McCoy, Michelle Tate, Jonathan Francois Patrice Ferrand, Kim A Lennox, Eicke Latz, Bryan Raymond George Williams, Michael Paul Marie Gantier

Research output: Contribution to journalArticleResearchpeer-review

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1177-1188
Number of pages12
JournalNucleic Acids Research
Volume43
Issue number2
DOIs
Publication statusPublished - 30 Jan 2015

Cite this

Sarvestani, Soroush ; Stunden, Hilary James ; Behlke, Mark A ; Forster, Samuel ; McCoy, Claire ; Tate, Michelle ; Ferrand, Jonathan Francois Patrice ; Lennox, Kim A ; Latz, Eicke ; Williams, Bryan Raymond George ; Gantier, Michael Paul Marie. / Sequence-dependent off-target inhibition of TLR7/8 sensing by synthetic microRNA inhibitors. In: Nucleic Acids Research. 2015 ; Vol. 43, No. 2. pp. 1177-1188.
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Sequence-dependent off-target inhibition of TLR7/8 sensing by synthetic microRNA inhibitors. / Sarvestani, Soroush; Stunden, Hilary James; Behlke, Mark A; Forster, Samuel; McCoy, Claire; Tate, Michelle; Ferrand, Jonathan Francois Patrice; Lennox, Kim A; Latz, Eicke; Williams, Bryan Raymond George; Gantier, Michael Paul Marie.

In: Nucleic Acids Research, Vol. 43, No. 2, 30.01.2015, p. 1177-1188.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Tate, Michelle

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