ABSTRACT
Recent years have seen the rapid rise of RNA interference as a powerful tool to silence gene expression at the post-transcriptional level. The most widely-employed technique to initiate RNA interference is the delivery of small interfering RNAs into the cytosols of target cells. Next to knock-down studies in vitro, high hopes surround the development of gene-specific drugs to prevent or cure human disease, although a number of studies have raised serious concerns about the specificity and safety of siRNA applications in vitro and in vivo. One major unanticipated and unwanted effect is the activation of the immune system upon siRNA application. In addition to potential dose limiting toxicities in vivo, siRNA-mediated activation of the immune system can produce a pleiotropy of secondary responses, thereby masking specific effects. This chapter reviews the problem of non-specific recognition of siRNAs by the immune system, along with our current understanding of the underlying mechanisms. We tackle the question of how RNAi can coexist with characterized RNA recognition pathways of the innate immune system, and highlight ways in which immune recognition can be bypassed when employing RNAi. Extending our knowledge on these intriguing topics is an inevitable prerequisite before this touted technology can be introduced as an innovative clinical therapeutic tool.
