Preeclampsia (PE), diagnosed by hypertension and proteinuria at or after the 20 th week of gestation, is mediated in part by excessive immune system activation and inflammation. Ligand binding of the double-stranded RNA (dsRNA) receptors RIG-1, MDA-5, and TLR3 leads to innate immune system activation and inflammation. However, whether activation of all three receptors contributes to the development of PE is unknown. In placentas of women with PE there was significantly increased expression of all three dsRNA receptors as well as dsRNA compared to placentas of normotensive women. Poly I:C (a viral dsRNA mimetic) treatment in control mice on days 13, 15, and 17 induced pregnancy-dependent hypertension (P-PIC SBP: 1475 mmHg vs. P SBP: 1004 mmHg, p<0.05), endothelial dysfunction, fetal demise and altered immune cell subsets. This was associated with increased placental protein levels of all three dsRNA receptors compared to normal pregnant mice (RIG-1: 47%, MDA-5: 59%, and TLR3: 86%, p<0.05 vs. controls). Splenic levels of the anti-inflammatory immune cells CD4+/CD25+ regulatory T cells (Tregs) and CD11b+/CD14- myeloid-derived suppressor cells (MDSCs) decreased significantly while the pro-inflammatory immune cells CD11b+ monocytes, CD3+/ T cells, and CD11c+ dendritic cells were increased significantly in P-PIC compared to P mice. In pregnant, poly I:C-treated TLR3KO mice SBP was decreased significantly compared to P-PIC mice but not fully restored (P-PIC TLR3KO: 1103 mmHg). P-PIC TLR3KO mice exhibited significantly reduced endothelial dysfunction and fetal demise compared to P-PIC mice, as well as significantly increased splenic CD4+/CD25+ Tregs and CD11b+/CD14- MDSCs and decreased CD11b+ monocytes, CD3+/ T cells, and CD11c+ dendritic cells. These results taken together suggest that activation of dsRNA receptors contribute to the development of PE-like symptoms in mice, but TLR3 deficiency alone did not completely prevent PE-like symptoms. Thus, RIG-1 and MDA-5 activation may play a partial role in blood pressure regulation during pregnancy.
