Interleukin-17 Signaling Mediates Cytolytic Natural Killer Cell Activation in Response to Placental Ischemia.

TH17s, IL-17, and cytolytic natural killer cells (cNKs) are increased in preeclampsia and contribute to the hypertension, inflammation, and fetal growth restriction that occurs in response to placental ischemia in the Reduced Uterine Perfusion Pressure (RUPP) rat model of preeclampsia. As IL-17 stimulates NK cytotoxicity in vitro, we tested the hypothesis that IL-17 inhibition in RUPP rats would decrease cNK activation as a mechanism to improve maternal and fetal outcomes. On gestation day (GD)14, rats undergoing RUPP received a mini-osmotic pump infusing IL-17RC (100 pg/day), a soluble IL-17 receptor (RUPP+IL-17RC). On GD19, mean arterial pressure (MAP) was measured in normal pregnant (NP), RUPP, and RUPP+IL-17RC rats (n=12/group), animals were sacrificed, and blood and tissues were collected for analysis. MAP was 30% higher in RUPP compared to NP (p<0.0001) and was 12% lower in RUPP+IL-17RC (p=0.0007 vs RUPP). Placental cytolytic NK cells were 132% higher in RUPP than in NP (p=0.04 vs NP) and were normalized in RUPP+IL-17RC (p=0.03 vs RUPP). Placental levels of TNF-alpha, a cNK-secreted cytokine, and MIP-3alpha, a cNK chemokine, were higher in RUPP vs NP, and lower after IL-17 blockade. Placental VEGF was lower in RUPP vs NP, and was normalized in RUPP+IL-17RC. In vitro cytolytic activity of RUPP placental NKs was higher compared to NP, and was blunted in RUPP+IL-17RC NKs. Finally, both fetal and placental weight were lower in RUPP compared to NP, and were improved in RUPP+IL-17RC. These data identify IL-17 as a mediator of cNK activation in response to placental ischemia during pregnancy.