The Chromosome 19 miRNA cluster guards trophoblasts against overacting innate immunity

To maintain pregnancy health, the human placenta delicately balances protection of the developing fetus from invading pathogens with suppression of excessive inflammation that could lead to fetal and neonatal autoimmune disorders. Previous research, including our own, has shown that small RNA products of the Chromosome 19 MicroRNA Cluster (C19MC) promote viral resistance in non-trophoblastic cells. However, the role of C19MC products in placental trophoblasts remained unclear. Here, we analyzed chromatin accessibility in the C19MC enhancer and identified a previously unknown regulatory domain. Deletion of this domain silenced the expression of C19MC microRNA and Alu elements in trophoblasts. This silencing unexpectedly led to marked activation of cellular innate immune response and strikingly increased Toll-like receptor 3 (TLR3)-mediated sensitivity to poly(I:C), a viral RNA mimic. Our data suggest that C19MC non-coding RNAs may interfere with endosomal TLR3 activation in trophoblasts, highlighting a previously unrecognized mechanism for hindrance of excessive innate immune activation.