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

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.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Sarvestani ST,Stunden HJ,Behlke MA,Forster SC,McCoy CE,Tate MD,Ferrand J,Lennox KA,Latz E,Williams BR,Gantier MP

doi

10.1093/nar/gku1343

subject

Has Abstract

pub_date

2015-01-01 00:00:00

pages

1177-88

issue

2

eissn

0305-1048

issn

1362-4962

pii

gku1343

journal_volume

43

pub_type

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