Gene silencing below the immune radar
Gunther Hartmann
Gunther Hartmann
Published February 23, 2009
Citation Information: J Clin Invest. 2009;119(3):438-441. https://doi.org/10.1172/JCI38475.
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Commentary

Gene silencing below the immune radar

Abstract

In vertebrates, the detection of viral nucleic acids is the first step toward innate and subsequent adaptive antiviral immune responses. A sophisticated, protein receptor–based sensor system has evolved to recognize viral nucleic acids and to trigger a variety of antiviral defense mechanisms. The more we learn about this elaborate sensor system, the more it becomes evident how difficult it is to introduce exogenous nucleic acids such as siRNA into cells without triggering antiviral immunoreceptors. In this issue of the JCI, Judge and colleagues provide evidence that siRNA can be designed and delivered in a way that allows specific and successful silencing of target genes in tumor cells in vivo, leading to tumor cell death and prolonged survival of tumor-bearing mice in the absence of immune activation (see the related article beginning on page 661). This study represents a major technological advance, setting new standards for well-controlled siRNA applications in vivo, and has the potential to guide clinical development toward siRNA therapeutics with well-defined and selective gene-silencing activities.

Authors

Gunther Hartmann

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Figure 2

Immunorecognition of RNA.

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Immunorecognition of RNA. RNA delivered to the endosome is detected by T...
RNA delivered to the endosome is detected by TLR3, in the case of long dsRNA or its mimic poly(I:C) and short dsRNA, or by TLR7, in the case of siRNA and single-stranded RNA (ssRNA). RNA delivered to the cytosol can be recognized by cytosolic helicases. The RNA helicase RIG-I detects RNA carrying a triphosphate group at the 5′ end (5′-PPP) and possibly blunt-end short RNA and intermediate dsRNA. Melanoma differentiation-associated protein-5 (MDA-5) detects long dsRNA. Long dsRNA also binds to RNA-binding PKR, but activation of IRF3 and IRF7 and subsequent type I IFN induction by PKR is controversial (as indicated by question mark). TLRs signal via TIR domain–containing adapter inducing IFN-β (TRIF) (in the case of TLR3) to activate IRF3 and NF-κB or via MyD88 (in the case of TLR7) to activate IRF7 and NF-κB. RIG-I and MDA-5 signal via IFN-β promoter stimulator-1 (IPS-1) to induce IRF7 and NF-κB. Depending on the cell type and its receptor expression pattern (e.g., ECs, myeloid DCs), recognition of RNA leads to the production of type I IFNs (e.g., IFN-α/β), and of proinflammatory cytokines or may lead to the modulation of cell-specific functions. In the study reported by Judge et al. (18) in this issue of the JCI, immunorecognition of siRNA is avoided by chemical modification and by the specific mode of delivery.