Abstract
The Reduced Uterine Perfusion Pressure (RUPP) rat model of placental ischemia mimics many of the characteristics of preeclampsia (PE) including hypertension, intrauterine growth restriction, and increases in circulating TH17 cells (TH17s), IL‐17 and placental cytolytic natural killer cells (cNKs). Although the stimulus for cNKs in PE is currently unknown, recent in vitro studies suggest that IL‐17 induces proliferation and cytolytic activity in human NK cells. We have previously demonstrated that placental ischemia (PI)‐stimulated TH17s mediate pathophysiology in pregnant rats similar to that seen in PE. In this study we tested the hypothesis that PI‐stimulated TH17s induce cNKs and their associated cytokines (IFNγ, TNFα) and cytolytic proteins (perforin, granzymes). We further hypothesized that inhibition of oxidative stress (ROS) with Tempol (Tp) would attenuate NK cytolytic activation. PI‐stimulated TH17s were isolated from RUPP and injected i.p. into normal pregnant (NP) rats on gestation day (GD) 12 with or without Tp administration ad libitum in drinking water (GD 12–19). Circulating TH17s and total NK cells (tNKs) and cNKs in placentas were quantified via flow cytometry in NP, NP+TH17, and NP+TH17+Tp rats. MAP, pup weight, placental ROS, cytokines, perforin and granzymes were measured. Circulating TH17s and IL‐17 were significantly increased after TH17 adoptive transfer. Circulating TH17s (% gated): NP (n=7) − 1.2±0.3%, NP+TH17 (n=7) − 4.2±0.8%, NP+TH17+Tp (n=7) − 0.8±0.2% (p<0.05 vs NP+TH17). MAP increased from 96.3±4.7 mmHg in NP to 117.9±2.2 mmHg in NP+TH17, and was normalized to 102±2.6 mmHg in NP+TH17+Tp (p<0.05 vs NP+TH17s). Placental tNKs (% gated) were significantly increased in NP+TH17 (19.7±4.6%) compared to NP (5.4±2.0%) and NP+TH17+Tp (3.1±1.3%; p<0.05 vs NP+TH17). Importantly, placental cNKs were significantly increased in response to TH17s (NP: 2.9±0.9% vs NP+TH17: 14.9 ±4.0%) and were inhibited with Tp treatment (2.8±1.0%; p<0.05 vs NP+TH17). Pup weight decreased from 2.4±0.04 mg in NP to 1.9±0.1 mg in NP+TH17 and increased to 2.3±0.04 mg in NP+TH17+Tp (p<0.05 vs NP+TH17). Placental ROS increased from 223.5±63 RLU in NP to 574.3±95.3 RLU in NP+TH17 and decreased to 247.8±71.5 RLU in NP+TH17+Tp (p<0.05 vs NP+TH17). Placental inflammation was significantly increased in response to PI‐stimulated TH17s and was attenuated with Tp treatment. Placental IFNγ: NP − 127.4±4.0 pg/mg, NP+TH17 − 153±16.6 pg/mg, NP+TH17+Tp − 116±4.0 pg/mg (p<0.05 vs NP+TH17); Placental TNFα: NP − 76.3±9.2 pg/mg, NP+TH17 − 129.8±11.1 pg/mg, NP+TH17+Tp − 61.5±21.1 pg/mg (p< 0.05 vs NP+TH17). Placental NK cytolytic proteins were significantly increased in response to PI‐stimulated TH17s. Placental perforin: NP − 0.3±0.2 pg/mg NP+TH17 − 1.6±0.2 pg/mg, NP+TH17+Tp − 1.2±0.7 pg/mg in (p<0.05 vs NP); Placental Granzyme A: NP − 91.6±18 pg/mg, NP+TH17 − 180.6±26.6 pg/mg, NP+TH17+Tp − 399.7±54.7 mg/pg (p<0.05 vs NP). These data suggest a role for PI‐stimulated TH17s to induce a cytotoxic phenotype in NKs during pregnancy and identifies stimulation of cNKs as a new mechanism by which TH17s may mediate PE pathophysiology.Support or Funding InformationNIH: HL130456, HD067541This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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