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Review
. 2017 Mar 23:8:331.
doi: 10.3389/fimmu.2017.00331. eCollection 2017.

RNA Interference-Induced Innate Immunity, Off-Target Effect, or Immune Adjuvant?

Zhongji Meng  1 , Mengji Lu  2
Affiliations
Review

RNA Interference-Induced Innate Immunity, Off-Target Effect, or Immune Adjuvant?

Zhongji Meng et al. Front Immunol. .

Abstract

RNA interference (RNAi) is a natural cellular mechanism that inhibits gene expression in a sequence-specific manner. In the last decade, RNAi has become a cornerstone in basic biological systems research and drug development efforts. The RNAi-based manipulation of mammalian cells facilitates target identification and validation; assists in identifying human disease etiologies; and expedites the development of treatments for infectious diseases, cancer, and other conditions. Several RNAi-based approaches are currently undergoing assessment in phase I and II clinical trials. However, RNAi-associated immune stimulation might act as a hurdle to safe and effective RNAi, particularly in clinical applications. The induction of innate immunity may originate from small interfering RNA (siRNA) sequence-dependent delivery vehicles and even the RNAi process itself. However, in the case of antagonistic cancers and viral infection, immune activation is beneficial; thus, immunostimulatory small interfering RNAs were designed to create bifunctional small molecules with RNAi and immunostimulatory activities. This review summarizes the research studies of RNAi-associated immune stimulation and the approaches for manipulating immunostimulatory activities.

Keywords: RNA interference; immunostimulatory RNA; immunostimulatory small interfering RNAs; innate immunity; small interfering RNA.

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Figures

Figure 1
Figure 1
Schematic representation of RNA interference (RNAi)-associated immunostimulation. The retinoic acid-inducible gene-I (RIG-I)/melanoma differentiation-associated protein 5 (MAD5), toll-like receptor (TLR) 3, TLR7/8, and PKR signaling pathways can recognize isiRNA; on the other hand, the RNAi process generates small RNAs that may activate PKR, TLR3, and TLR7/8, inducing type I interferon (IFN) and pro-inflammatory cytokine production. isiRNA, immunostimulatory siRNA.
Figure 2
Figure 2
Schematic representation of isiRNA and non-isiRNA. RNA sequence requirements of isiRNA and non-isiRNAs were shown; isiRNA may trigger toll-like receptor (TLR) 7/8, or retinoic acid-inducible gene-I (RIG-I)/melanoma differentiation-associated protein 5 (MAD5) signaling pathways, leading to activation of innate immunity. isiRNA, immunostimulatory siRNA; non-isiRNA, non-stimulatory siRNA.
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