IL‐17 Signaling Stimulates Natural Killer Cell Activation and Causes Mitochondrial Dysfunction in Response to TH17 Cells Stimulated in Response to Placental Ischemia During Pregnancy

Abstract

Preeclampsia (PE) is a multisystem disorder characterized by new onset hypertension that is associated with placental ischemia, mitochondrial (mt) dysfunction, and an imbalance in T helper and Natural Killer (NK) cells during pregnancy. The reduced uterine perfusion pressure (RUPP) model is an established model for PE exhibiting hypertension in response to placental ischemia associated with mt dysfunction and mt reactive oxygen species (ROS), activation of T helper and NK cells. We have previously shown an important role for IL‐17 in the hypertension and activation of NK cells in the RUPP rat. However we don’t know the role for IL‐17 or TH17 cells in contributing to NK cell mediated mt dysfunction and ROS associated with placental ischemia. Therefore, we hypothesize that hypertension in response to placental ischemia stimulated TH17 cells causes mt ROS mediated through IL‐17 signaling to NK cells. On gestation day 12 (GD12) RUPP‐induced TH17s (splenic CD4+/CD25− cells) were injected into normal pregnant (NP) rats. Recombinant mouse IL‐17 receptor C (IL‐17RC) (100 pg/day) was administered from GD14‐19 via osmotic mini‐pump. On GD19, samples were collected and mean arterial pressure (MAP) was measured. Mt respiration and mt ROS data was measured in isolated mitochondria from renal and placental tissues using the Oxygraph 2K and fluorescent microplate reader, respectively. A one‐way ANOVA with Bonferroni post hoc test was used for statistical analysis. MAP was increased in NP+RUPP TH17 recipient rats (110 ± 0.94mmHg, n=10) compared to NP controls (91 ± 3.6mmHg, n=11) (p<0.05), and was lowered with IL‐17RC (100± 2.4 mmHg, n=4). Circulating activated NK cells were significantly increased with RUPP TH17 (4.74± 0.9 %, n=5) (p<0.0001) compared to NP controls (0.08± 0.06 %, n=8), and were attenuated with IL‐17RC (0.00± 0.00 %, n=3) (p<0.001). Placental activated NK cells were significantly increased with RUPP TH17 (2.5± 1.01 %, n=4) (p<0.05) compared to NP controls (0.03± 0.03 %, n=8) and were attenuated with IL‐17RC (0.21± 0.12 %, n=4) (p<0.05). Renal mtROS increased in NP RUPP TH17 recipients (593 ± 110%, n=9) compared to NP controls (289 ± 30%, n=6), and was attenuated by IL‐17RC (380± 103%, n=3). Placental mtROS significantly increased in NP RUPP TH17 recipients (3081 ± 720%, n=7) (P<0.0005) compared to NP controls (1287 ± 231.3%, n=6) (p<0.0001), and was decreased by administration of IL‐17RC (561.7± 105.5 %, n=3) (p<0.0001). These data demonstrate that IL‐17 signaling plays an important role in NK cell activation and tissue mt function in response to TH17 cells stimulated during placental ischemia of pregnancy.Support or Funding InformationR01HD067541‐06, P20GM121334, AHA 19CDA34670055, T32HL105324