Journal
NUCLEIC ACIDS RESEARCH
Volume 43, Issue 2, Pages 1177-1188Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gku1343
Keywords
-
Categories
Funding
- Australian National Health and Medical Research Council (NIIMRC) [1022144, 1081167, 1062683]
- Australian Research Council [140100594]
- Victorian Government's Operational Infrastructure Support Program
- National Health and Medical Research Council of Australia [1081167] Funding Source: NHMRC
Ask authors/readers for more resources
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 AMO stargeting 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available