IL-33 inhibition increases T_H17 and cNK cells and decreases T_reg populations to contribute to hypertension in pregnant rats

Preeclampsia (PE), a leading cause of maternal/fetal morbidity and mortality characterized by chronic immune activation and endothelial dysfunction, is a hypertensive pregnancy disorder with end-organ damage that manifests after 20 gestational weeks. Previously, we demonstrated IL-33 signaling may link NLRP3 activation to T_H17 and cytolytic NK (cNK) activation in PE; and clinical studies have reported reduced IL-33 signaling in PE. We investigated the role of IL-33 signaling in directly mediating PE pathophysiology by inhibiting IL-33 from gestation day 14-19 using i.p. administration of ST2 (IL-33 decoy receptor) and of an IL-33 neutralizing antibody. We hypothesized IL-33 blockade in pregnancy would induce cNK and T_H17 activation and inflammation leading to endothelial dysfunction and maternal hypertension. We assessed maternal BP, uterine artery resistance (UARI), cNK, T_reg, T_H17, and cNK cytotoxicity in normal pregnant, ST2, and anti-IL-33 antibody rats. We found BP and UARI increased after ST2 and anti-IL-33 infusion. Circulating and placental cNK and T_H17 increased and T_reg decreased in ST2 and anti-IL-33 treated groups. cNK cytotoxicity was also higher in ST2 and anti-IL33 groups. These findings demonstrate a role for IL-33 signaling in controlling vascular function and BP during pregnancy possibly by mediating innate and adaptive immune inflammatory responses. These data identify the IL-33 signaling pathway as a potential therapeutic target in managing PE.