IMR Press / FBL / Volume 13 / Issue 11 / DOI: 10.2741/3011

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Article
Does the understanding of immune activation by RNA predict the design of safe siRNAs?
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1 Institute for Cancer Research, Department of Immunology, Molecular Medicine Group, Montebello, N-0310 Oslo, Norway

*Author to whom correspondence should be addressed.

 

Front. Biosci. (Landmark Ed) 2008, 13(11), 4379–4392; https://doi.org/10.2741/3011
Published: 1 May 2008
Abstract

The innate immune system uses pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) to recognize conserved pathogen-associated molecular patterns (PAMPs) expressed by microbes and to activate the initial phase of immune response. Both bacterial and viral nucleic acids activate TLRs resulting in cytokines and interferon production. Recent studies indicated that unmodified small interfering RNAs (siRNAs) corresponding to either mammalian (self) or microbial (non-self) RNA sequences can activate immunity through TLR7/8 in a sequence-dependent manner. Hence, the use siRNAs in humans will require understanding the mechanisms involved in the discrimination between self and non-self RNAs. In the case where immunostimulation is not wanted, chemical modifications can prevent immune activation and reduce off-target effects, while preserving siRNA silencing potency. Interestingly, 2'-O-methyl modified RNAs not only evade immune sensing, but antagonize with immunostimulatory single- or double-stranded siRNAs to activate innate immunity. This review highlights the recent progress in understanding the siRNA sensing by innate immunity and presents a range of strategies allowing either the design of siRNAs with minimal or maximal immunostimulatory potency for therapeutic applications.

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