Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, QC, H3C 3J7, Canada.
Canadian National Transplant Research Program, Edmonton, Alberta, T6G 2E1, Canada.
Sci Rep. 2019 May 10;9(1):7203. doi: 10.1038/s41598-019-43591-y.
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 vesicles upon 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 sequencing of total RNA, we report that apoptotic bodies and ApoExos are loaded with divergent RNA cargos that are not released by healthy endothelial cells. Apoptotic bodies, like endothelial cells, contain mainly ribosomal RNA whereas ApoExos essentially contain non-ribosomal non-coding RNAs. Endogenous retroelements, bearing viral-like features, represented half of total ApoExos RNA content. ApoExos also contained several copies of unedited Alu repeats and large amounts of non-coding RNAs with a demonstrated role in autoimmunity such as U1 RNA and Y RNA. Moreover, ApoExos RNAs had 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 RNAs that can stimulate a variety of RIG-I-like receptors and endosomal TLRs. Hence, apoptotic endothelial cells selectively sort in ApoExos a diversified repertoire of immunostimulatory "self RNAs" that are tailor-made for initiation of innate immune responses and autoimmunity.
内皮细胞与免疫系统有着多方面的相互作用，既是免疫反应的启动者，也是免疫反应的靶标。在体内，凋亡的内皮细胞在 caspase-3 激活后会释放两种类型的细胞外囊泡：凋亡小体和类外泌体纳米囊泡（ApoExos）。只有 ApoExos 具有免疫原性：它们的注射会导致小鼠炎症和自身免疫。基于总 RNA 的深度测序，我们报告说凋亡小体和 ApoExos 携带了不同的 RNA 货物，这些货物不会被健康的内皮细胞释放。凋亡小体与内皮细胞一样，主要含有核糖体 RNA，而 ApoExos 则主要含有非核糖体非编码 RNA。内源性逆转录元件，具有类似病毒的特征，占 ApoExos RNA 总量的一半。ApoExos 还包含几个未经编辑的 Alu 重复序列的拷贝，以及大量在自身免疫中具有明确作用的非编码 RNA，如 U1 RNA 和 Y RNA。此外，ApoExos RNA 具有独特的核苷酸组成和二级结构，其特点是富含 U 丰富的基序和不稳定折叠的 RNA。总体而言，ApoExos 被加载了可以刺激多种 RIG-I 样受体和内体 TLR 的 RNA。因此，凋亡的内皮细胞选择性地将多样化的免疫刺激“自身 RNA”分拣到 ApoExos 中，这些 RNA 是为先天免疫反应和自身免疫的启动而量身定制的。
