Abstract
Preeclampsia, new-onset hypertension with proteinuria or end-organ dysfunction after 20 wk gestation, is associated with placental ischemia, maternal endothelial dysfunction, and chronic inflammation. Preeclamptic women and the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia have higher placental expression and activation of NLRP3 inflammasome and its associated cytokine, interleukin 1β (IL-1β). We hypothesized that higher IL-1β signaling through the IL-1 receptor type 1 (IL-1R1), contributes to maternal hypertension, fetal growth restriction (FGR), and endothelial dysfunction in response to placental ischemia. GD14 timed-pregnant Sprague-Dawley rats underwent RUPP or sham surgery with implantation of minipumps infusing IgG or IL-1R1 neutralizing antibody (αIL-1R1; 2 μg/kg/day). On GD19, mean arterial pressure (MAP), fetal and placental weights, blood, and tissues were collected. Plasma IL-1β was higher in RUPP vs. Sham IgG controls (8.79 ± 2.01 vs. 3.24 ± 1.05 pg/mL; P < 0.01) and normalized in RUPP + αIL-1R1 (1.23 ± 0.51 pg/mL; P < 0.01 vs. RUPP + IgG). MAP was higher at 120 ± 4 mmHg in RUPP + IgG from 100 ± 3 mmHg in Sham + IgG (P < 0.01). αIL-R1 treatment reduced MAP to 106 ± 12 mmHg in RUPP (P < 0.01 vs. RUPP + IgG). RUPP + IgG placenta weight (0.46 ± 0.1 g) was lower than Sham + IgG (0.54 ± 0.1 g; P < 0.01) and significantly higher in RUPP + αIL-R1 (0.52 ± 0.02 g; P < 0.05 vs. RUPP + IgG). Fetal weight was higher in RUPP + αIL-1R1 (2.77 ± 0.22 g) vs. control RUPP (1.97 ± 0.11 g; P < 0.01). Placental cNK, TH17s, and macrophages were higher, and TRegs were lower in RUPP + IgG vs. Sham, and were normalized in RUPP + αIL-1R1 (P < 0.05). IL-1R1 inhibition decreased IL-1R1 expression but did not reverse RUPP-induced changes in NFκB, preproendothelin, or endothelial nitric oxide synthase expression. IL-R1 activation contributes to maternal hypertension and FGR via mediating immune populations during ischemia.NEW & NOTEWORTHY IL-1R1 inhibition in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia lowered maternal blood pressure, reduced fetal reabsorptions, and improved fetal and placental growth. These effects were accompanied by restored systemic and placental immune balance but no improvement in vascular markers such as VEGF or preproendothelin. Thus, IL-1R1 blockade, including the clinical agent anakinra, is a promising therapeutic avenue that may require combination strategies for optimal benefit.
Keywords:
hypertension; inflammation; interleukin 1 receptor type 1; placental ischemia; preeclampsia.