Interleukin-17 signaling mediates cytolytic natural killer cell activation in response to placental ischemia

Abstract

Interleukin-17 signaling mediates cytolytic natural killer cell activation in response to placental ischemia. Am J Physiol Regul Integr Comp Physiol 318: R1036-R1046, 2020. First published April 22, 2020; doi:10.1152/ajpregu.00285.2019.-T-helper (TH)17s, 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 miniosmotic 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 10-12/group), animals were euthanized, and blood and tissues were collected for analysis. MAP was 30% higher in RUPP compared with 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-, a cNKsecreted cytokine, and macrophage inflammatory protein-3 (MIP-3), 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 with NP and was blunted in RUPP IL-17RC NKs. Finally, both fetal weight and placental weight were lower in RUPP compared with 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.