Sunday, May 11, 2025
5/11/2025
The role of IL-33 signaling in the pathophysiology of preeclampsia - Project Summary/Abstract Preeclampsia (PE) is a pregnancy specific disorder characterized by the development of hypertension in combination with end-organ dysfunction after 20 weeks of gestation. The prevalence of this disorder has continuously increased over the past 20 years and it is a leading cause of fetal and maternal morbidity. Despite the burden PE causes on maternal and fetal health, no effective treatment for PE exists other than delivery of the fetal-placental unit and there is an urgent need to understand PE pathophysiology in order to identify potential therapeutic targets. It is known that altered immune responses contribute to PE pathophysiology. However, the mechanisms underlying and contributing to those altered responses are not well understood though clinical studies have identified elevated activation of the NLRP3 inflammasome as a potential contributor to altered immune responses. The Reduced Uterine Perfusion Pressure (RUPP) model of placental ischemia, which our lab uses, is a widely acknowledged model and recapitulates many characteristics of human PE. Using this model, our preliminary data shows NLRP3 mediates increases in maternal blood pressure, intrauterine growth restriction, and TH17 and cytolytic NK (cNK) cell activation in RUPP rats. This is consistent with studies on NLRP3 activation in other inflammatory disease processes, which also show increased NLRP3 activation causing increased TH17 and cNK cell activation. Previous studies propose NLRP3 activation achieves TH17 and cNK cell activation through inhibition of IL-33 signaling, a signaling pathway known to inhibit TH17 and cNK cell activation. Our preliminary data links aberrant IL-33 signaling to NLRP3 activation and shows supplementation of IL-33 in RUPP rats results in lower maternal blood pressure, improved intrauterine growth restriction, and decreased activation of TH17 and cytolytic NK cells. This data supports the ideas detailed in this proposal. The central hypothesis behind this proposal is placental ischemia induced NLRP3 activation impairs IL-33 signaling to induce TH17 and cNK cell activation leading to inflammation and oxidative stress to cause vascular dysfunction and the development of maternal hypertension and intrauterine growth restriction. This hypothesis will be tested through the following specific aims using both in vivo and in vitro techniques. Specific aim 1: Test the hypothesis that decreased IL-33 signaling mediates TH17 and cytolytic NK cell activation, inflammation, and oxidative stress leading to vascular dysfunction, and the development of maternal hypertension and IUGR in response to placenta ischemia. Specific aim 2: Test the hypothesis that blockade of IL-33 signaling in pregnant rats will induce TH17 and cytolytic NK cell activation, inflammation, and oxidative stress leading to vascular dysfunction, and the development of hypertension and IUGR.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).