Inhibition of caspase 1 reduces blood pressure, cytotoxic NK cells, and inflammatory TH17 cells in placental ischemic rats

Abstract

Preeclampsia (PE) is characterized by maternal hypertension, fetal growth restriction (FGR), and increased inflammation and immune activation, including cytotoxic NK cells (cNKs) and inflammatory T-Helper17 cells (T H 17s). Caspase 1 activity directly leads to release of the inflammatory cytokines IL1β and IL18. Using the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia, we tested the hypothesis that inhibition of caspase 1 with Belnacasan in RUPP rats will attenuate PE pathophysiology. On gestation day (GD) 14, timed pregnant 10–12-week-old Sprague Dawley rats underwent the RUPP or Sham procedure and received either vehicle or Belnacasan (50mg/kg) daily i.p. from GD14 through GD19: RUPP + vehicle, RUPP + Belnacasan, Sham + vehicle, Sham + Belnacasan. Carotid catheters were placed on GD18. On GD19, MAP was measured, animals were euthanized, and blood and tissues were collected for analysis. Bioplex and flow cytometry analysis were performed on placental tissues. Placental IL1β was markedly increased in RUPP rats vs. Sham rats (44.2 vs. 21.67 pg/mg, p=0.0009). Belnacasan treatment significantly reduced IL1β in RUPP rats (21.90 pg/mg; p=0.0006 vs RUPP). Likewise, placental IL18 was increased in RUPP rats vs Sham (27.1 vs 6.7 pg/mg, p=0.007), and inhibition of caspase 1 reduced RUPP IL18 (6.2, p=0.01 vs RUPP) to Sham levels. No significant differences in IL1β or IL18 were observed in treated Sham rats. These data show the administered Belnacasan dose is effective against Caspase 1 activity. Caspase 1 inhibition reduced placental cNKs in treated-RUPP vs control RUPP (0.155% vs. 0.362 % gated; p=0.043). Belnacasan treatment also reduced placental T H 17s in RUPP rats vs. control RUPPs (1.053% vs 7.25% gated; p=0.003). Increased MAP was observed in RUPP rats vs Sham (131.5 mmHg vs 104.8 mmHg; p<0.0001) and was reduced in RUPP + Belnacasan (117.5 mmHg; p=0.0016 vs RUPP). No changes were observed in MAP of Sham rats treated with Belnacasan. Placental reactive oxygen species (ROS) were elevated in RUPP vs Sham (456.4 vs 198.8 RLU/min/mg, p=0.029). Caspase 1 inhibition significantly reduced ROS in treated RUPP rats (210.3, p=0.031) vs RUPP), and had no effect on ROS in treated Sham rats (156.3). Caspase 1 inhibition had no effect on fetal weight or placental efficiency in any groups. Additional analyses will include assessment of other cytokines in blood and tissue, as well as vascular function in all groups. In conclusion, caspase 1 inhibition reduces placental T H 17 and cNK populations and reduces MAP in RUPP rats. These data suggest that caspase 1 is a key contributor to PE pathophysiology and may represent a therapeutic target to improve maternal outcomes in PE. This work was supported by National Institutes of Health Grants T32HL105324 to C. A. Shields, F31HL165852 to Xi Wang, and R01HL151407 to D. C. Cornelius. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.