IL-1 Receptor Type 1 Signaling Reduces Maternal Immunotolerant Regulatory T Cells and Contributes to Placental Ischemia-Induced Maternal Hypertension and Fetal Growth Restriction
Abstract Body: Preeclampsia (PE), new-onset hypertension (HTN) after 20 weeks of gestation accompanied by proteinuria or other end-organ dysfunction, is characterized by placental ischemia, maternal endothelial dysfunction, and chronic inflammation. Like women with PE, the Reduced Uterine Perfusion Pressure (RUPP) rat model of placental ischemia displays increased placental expression and activation of NLRP3 inflammasome and its associated cytokine, IL-1β. However, the role of IL-1β signaling in PE pathophysiology is unknown. We hypothesized that increased IL-1β signaling through the IL-1 receptor (IL-1R1), contributes to maternal HTN, fetal growth restriction, and endothelial dysfunction in response to placental ischemia. GD14 timed-pregnant rats underwent RUPP or sham surgery with implantation of minipumps infusing IL-1R1 neutralizing antibody (αIL-1R1) or control IgG (2ug/kg/day; Sham+IgG, Sham+αIL-1R1, RUPP+IgG, RUPP+αIL-1R1; n=8/group). On GD19, MAP, fetal and placental weights, blood, and tissues were collected for assessment of plasma IL-1β, immune cells, and vasoactive mediators. Statistical analysis was via two-way ANOVA and data are presented as mean±SEM. MAP increased to 120±4mmHg in RUPP+IgG from 100±3mmHg in Sham+IgG (p<0.01). αIL-R1 significantly reduced MAP to 106±12 mmHg in RUPP+αIL-R1 (p<0.01 vs. RUPP+IgG). RUPP+IgG placenta weight (0.46±0.1g) was lower compared to Sham+IgG (0.54±0.1g; p<0.01) and significantly improved in Rupp+αIL-R1 (0.52±0.02g; p<0.05 vs RUPP+IgG). Fetal weight was also improved after IL-1R1 inhibition in RUPP (2.77±0.22 g) vs control RUPP (1.97±0.11g; p<0.01). Plasma IL-1β significantly increased in RUPP vs Sham IgG controls (8.79±2.01 vs 3.24±1.05 pg/mL; p<0.01) and was normalized in RUPP+αIL-1R1 (1.23±0.51 pg/mL;p<0.01 vs RUPP+IgG). Circulating and placental TRegs were reduced in RUPP+IgG vs Sham similar to women with PE. TRegs were significantly increased in both blood and placenta in RUPP+αIL-1R1 (p<0.05). Cytotoxic NK cells or TH17 were increased in blood and placenta of control RUPP rats, but IL-1R1 treatment did not attenuate the increased placental cNK or TH17 cells in RUPP. Additionally, IL-1R1 inhibition did not decrease pre-proendothelin expression or reactive oxygen species in treated RUPP. Placental Ischemia induced reductions of eNOS, phosphorylated eNOS, and VEGF were not improved in RUPP+αIL-1R1. IL-1R1 activation contributes to PE- pathophysiology by reducing maternal immunotolerant TRegs during placental ischemia.
Robbins, Marcus
( UNIVERSITY OF MISSISSIPPI MEDI
, Jackson
, Mississippi
, United States
)
Thompson, Deanna
( UNIVERSITY OF MISSISSIPPI MEDI
, Jackson
, Mississippi
, United States
)
Mckay, Jie
( UNIVERSITY OF MISSISSIPPI MEDI
, Jackson
, Mississippi
, United States
)
Mauroner, Jessica
( UNIVERSITY OF MISSISSIPPI MEDI
, Jackson
, Mississippi
, United States
)
Parker, Azaziah
( UNIVERSITY OF MISSISSIPPI MEDI
, Jackson
, Mississippi
, United States
)
Wilson, Rachel
( UNIVERSITY OF MISSISSIPPI MEDI
, Jackson
, Mississippi
, United States
)
Williams, Jan
( UNIVERSITY OF MISSISSIPPI MEDI
, Jackson
, Mississippi
, United States
)
Cornelius, Denise
( UNIVERSITY OF MISSISSIPPI MEDI
, Jackson
, Mississippi
, United States
)
Author Disclosures:
Marcus Robbins:DO NOT have relevant financial relationships
| Deanna Thompson:No Answer
| Jie McKay:No Answer
| Jessica Mauroner:No Answer
| Azaziah Parker:No Answer
| Rachel Wilson:No Answer
| Jan Williams:DO NOT have relevant financial relationships
| Denise Cornelius:DO NOT have relevant financial relationships
