RNA-triggered innate immunity: friend and foe

Endogenous, or <i>'self'</i>, vs. microbial, or <i>'non-self'</i>, RNA sensing can tip the scales between immune pathology and effective immunity. Cells are equipped to sense RNA, fundamental to trigger an innate immune response to clear viral infection that should not generate a harmful immune response against endogenous RNA. Multiple chemical modifications in RNA fine-tune its cellular sensing and are exploited by pathogens to evade immunity. Likewise, perturbations triggering self RNA sensing cause immune pathologies. This underscores the clinical need for a better understanding of self RNA recognition. Here, we address nucleic acid sensing in the innate immune response from an RNA-centric view. We discuss how self RNA is shielded from sensing by chemical modifications and subcellular compartmentalization, possible mechanisms and consequences of self-RNA sensing, and how this knowledge has been harnessed to revolutionize vaccine development.