Abstract P318: miR-155 Induces Inflammation by Polarizing M1 Macrophages in a TLR3-induced Preeclamptic Mouse Model

Abstract

Placental microRNA (miRNA) expression is known to be dysregulated during preeclampsia (PE), a hypertensive pregnancy disorder but the role it plays in the pathogenesis of PE is currently unknown. We have previously demonstrated that placental miR-155 expression is upregulated (P-PIC: 3.15 fold, p<0.05 vs. controls) in a TLR3-induced PE mouse model similar to PE patients. In addition, poly I:C (PIC) treatment significantly increased systolic blood pressure (SBP) at gestational day 17 in P-PIC WT (147±4.5 mmHg) compared to P WT mice (103±2.7 mmHg), but did not have any effect in P-PIC miR-155 KO mice (101±2 mmHg). In PE there is an increase in the number of total and activated macrophages. M1 macrophages display the capacity to shift T cell responses toward a TH1 while M2 macrophages promote a TH2 response. We hypothesized that TLR3-induced upregulation of miR-155 contributes to hypertension in part by polarizing the macrophages to a M1 phenotype and these effects will be attenuated in P-PIC miR-155 KO mice. Placental flow cytometry analyses demonstrate that administration of poly I:C induced CD45(+) CD11b(+) macrophages in P-PIC WT mice which is attenuated in P-PIC miR-155 KO mice. In addition, placental classical ‘M1’ macrophages CD45(+) CD11b(+) CD86(+) CD206(-) were increased and alternate ‘M2’ macrophages CD45(+) CD11b(+) CD206(+) CD86(-) were decreased in P-PIC WT mice compared to controls. Interestingly, administration of poly I:C did not change M1 macrophages but increased M2 macrophages in P-PIC miR-155 KO mice. P-PIC WT mice exhibited increased placental expression of additional M1 markers (NOS2, IFNg) and decreased expression of M2 markers (Arg1, IL-10) compared to controls by qRTPCR but not in P-PIC miR-155 KO mice. The above observations are also consistent with our splenic flow cytometry and qRTPCR studies. Based on our results, miR-155 activation induces inflammation in part by increasing M1 macrophages thus contributing to hypertension. Targeting the innate immune system by inhibition of monocyte/macrophages may have beneficial cardiovascular effects in women with PE.