Apoptotic endothelial cells release small extracellular vesicles loaded with immunostimulatory viral-like RNAs
2019
Endothelial cells have multifaceted interactions with the immune system, both as initiators and targets of immune responses. In vivo, apoptotic endothelial cells release two types of
extracellular vesiclesupon caspase-3 activation: apoptotic bodies and
exosome-like nanovesicles (ApoExos). Only ApoExos are immunogenic: their injection causes inflammation and autoimmunity in mice. Based on
deep sequencingof total
RNA, we report that apoptotic bodies and ApoExos are loaded with divergent
RNAcargos that are not released by healthy endothelial cells. Apoptotic bodies, like endothelial cells, contain mainly ribosomal
RNAwhereas ApoExos essentially contain non-ribosomal
non-coding RNAs. Endogenous retroelements, bearing viral-like features, represented half of total ApoExos
RNAcontent. ApoExos also contained several copies of unedited Alu repeats and large amounts of
non-coding RNAswith a demonstrated role in autoimmunity such as U1
RNAand
Y RNA. Moreover, ApoExos
RNAshad a unique nucleotide composition and secondary structure characterized by strong enrichment in U-rich motifs and unstably folded
RNAs. Globally, ApoExos were therefore loaded with
RNAsthat can stimulate a variety of
RIG-I-like receptorsand endosomal TLRs. Hence, apoptotic endothelial cells
selectively sortin ApoExos a diversified repertoire of immunostimulatory “self
RNAs” that are tailor-made for initiation of innate immune responses and autoimmunity.
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