Abstract 037: A Role for IL-17 to Activate Cytolytic Natural Killer Cells in Response to Placental Ischemia

Abstract

Women with preeclampsia (PE), newly developed hypertension and renal dysfunction during pregnancy, have small-for-gestational-age babies and demonstrate an increase in the inflammatory cytokine IL-17, placental oxidative stress, and cytolytic natural killer (NK) cell activation. The stimulus of the cytolytic NK cell phenotype during PE is currently unknown. Moreover, the specific role of cytolytic NK cells in the pathophysiology of preeclampsia has not been clearly defined. The reduced uterine perfusion pressure (RUPP) model of placental ischemia exhibits many of the characteristics of preeclampsia including hypertension, renal dysfunction, chronic inflammation and intrauterine growth restriction (IUGR). In this study, we tested the hypothesis that placental ischemia results in cytolytic activation of NK cells, and examined a role for the increased IL-17, in response to placental ischemia, to activate cytolytic NK cells. In this study, blood pressure (MAP) and pup weight were measured, and PBMCs and placental lymphocytes were examined via flow cytometry for surface makers of cytolytic NK cell activation. MAP significantly increased in response to placental ischemia from 103±4.1 mmHg in NP (n=6) to 129.1±3.1 mmHg (n=8) in RUPP rats (p<0.001). Neutralization of IL-17 with a soluble receptor attenuated the blood pressure response to 106.3±2.3 mmHg in RUPP+IL-17RC rats (n=3). Pup weight is significantly decreased in RUPP rats (2.52±0.18g in NP vs 2.03±0.05g in RUPP (p<0.05)), which increased to 2.54±0.36g in RUPP+IL-17RC. Cytolytic activation of circulating NK cells was not significantly changed among any of the groups (NP: 2.49±1.1%; RUPP: 7.74±3.2%; RUPP+IL-17RC:5.50±2.8%). However, cytolytic activation of placental NK cells increased in response to placental ischemia (NP: 3.4±1.1% vs RUPP 10.0±3.4%), and was completely attenuated after treatment with the soluble IL-17 receptor (RUPP+IL-17RC: 0.33±0.17%). These results suggest a role for placental ischemia and increased IL-17 to stimulate cytolytic NK cells. Furthermore, this study links the IL-17 pathway with cytolytic NK cell activation and IUGR in response to placental ischemia, potentially identifying new therapeutic targets to improve maternal and fetal outcomes of PE.