Syncytiotrophoblast 5’-tRNA fragments are placental endocrine signals contributing to sterile inflammation in preeclampsia

The relationship between placental pathology and the maternal syndrome of preeclampsia is incompletely characterised. Mismatch between placental nutrient supply and fetal demands induces stress in the syncytiotrophoblast, the layer of placenta in direct contact with maternal blood. Such stress alters the content and increases the release of extracellular vesicles into the maternal circulation. 5’-tRNA fragments (5’-tRF) constitute the majority of short RNA in these vesicles. Here we characterise 5’-tRF profiles in syncytiotrophoblast vesicles in preeclampsia, reporting differential expression of >900 fragments. We detected preeclampsia-dysregulated 5’-tRF in peripheral plasma, where we identified a placentally-derived load. We demonstrated these 5’-tRF induce sterile inflammation in macrophages and monocytes. Our findings suggest syncytiotrophoblast-derived 5’-tRF may contribute to distant vascular inflammation, previously described in preeclampsia. This is the first demonstration of endocrine actions of vesicle-bound 5’-tRF, which may have relevance in other disciplines studying their functions, such as immunology and cancer biology. ### Competing Interest Statement YMDL holds equity in DRA, Insighta Grail/Illumina and Take2. PJ holds equity in Illumina. PJ is a consultant to Take2. PJ is a Director of DRA and KingMed Future. YMDL, PJ, and LJ receives royalties from Illumina, LabCorp, Grail, DRA, Xcelom and Take2.