How does an RNA selfie work? EV-associated RNA in innate immunity as self or danger

Innate immunity is a first line of defence against danger. Exogenous pathogen- or microbe-associated molecular patterns (PAMPs or MAMPs) trigger innate immune responses through well-understood cellular pathways. In contrast, endogenous damage-associated molecular patterns (DAMPs) convey “danger signals” via their (mis)localization or modification. Both MAMPs and DAMPs are often communicated on or within extracellular vesicles (EVs). Despite growing evidence for the importance of EVs and their cargo in modulating innate immune responses, in some cases, it is unclear how EV-transported molecules are sensed as abnormal. In particular, EVs constitutively carry RNA, which is also abundant in the cytoplasm. How, then, would RNA convey a danger signal as a cargo of EVs? In this Perspective, we offer some thoughts on how EV-associated RNAs might raise the alarm for innate immune responses – or silence them.