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Published on: January 26, 2024
IL-33 Signaling Inhibition Leads to a Preeclampsia-Like Phenotype in Pregnant Rats
Xi Wang1, Corbin A Shields1, Deanna Thompson1
1Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Insights
Inhibiting Interleukin-33 (IL-33) signaling worsened preeclampsia symptoms, increasing blood pressure and oxidative stress. This suggests IL-33 is crucial for maintaining healthy pregnancy vascular function.
Area of Science:
- Immunology
- Reproductive Medicine
- Vascular Biology
Background:
- Preeclampsia (PE) is a pregnancy disorder causing maternal and fetal mortality, characterized by vascular dysfunction, oxidative stress, and inflammation.
- Aberrant immune responses are implicated in PE pathophysiology, with the IL-33 signaling pathway being a potential mediator.
- Current treatments for PE are limited to delivery, highlighting the need for understanding its underlying mechanisms.
Purpose of the Study:
- To investigate the impact of inhibiting IL-33 signaling on key immune cell populations (cytotoxic natural killer cells [cNK], T helper 17 cells [TH17], and regulatory T cells [TReg]).
- To assess the effects of IL-33 inhibition on vascular function, specifically maternal blood pressure and uterine artery resistance.
- To examine the influence of IL-33 signaling on oxidative stress markers in the kidneys and placenta.
Main Methods:
- IL-33 signaling was inhibited using recombinant ST2 (a decoy receptor) and a neutralizing antibody.
- Maternal blood pressure and uterine artery resistance index were monitored.
- Levels of oxidative stress, cytokine profiles, and pre-proendothelin-1 were measured in renal and placental tissues.
Main Results:
- Inhibition of IL-33 signaling led to increased maternal blood pressure and uterine artery resistance.
- Placental and renal oxidative stress markers were elevated following IL-33 inhibition.
- Immune cell populations shifted, with increased cNK and TH17 cells and decreased TReg cells in both placental and circulation.
Conclusions:
- IL-33 signaling plays a critical role in regulating vascular function and maternal blood pressure during pregnancy.
- The IL-33 pathway influences innate and adaptive immune responses relevant to PE pathophysiology.
- Targeting the IL-33 signaling pathway presents a potential therapeutic strategy for preeclampsia management.
Problem:
Preeclampsia (PE) is a hypertensive pregnancy disorder that is a leading cause of maternal and fetal morbidity and mortality characterized by maternal vascular dysfunction, oxidative stress, chronic immune activation, and excessive inflammation. No cure exists beyond delivery of the fetal-placental unit and the mechanisms driving pathophysiology are not fully understood. However, aberrant immune responses have been extensively characterized in clinical studies and shown to mediate PE pathophysiology in animal studies. One pathway that may mediate aberrant immune responses in PE is deficiencies in the IL-33 signaling pathway. In this study, we aim to investigate the impact of IL-33 signaling inhibition on cNK, TH17, and TReg populations, vascular function, and maternal blood pressure during pregnancy.
Method Of Study:
In this study, IL-33 signaling was inhibited using two different methods: intraperitoneal administration of recombinant ST2 (which acts as a decoy receptor for IL-33) and administration of a specific IL-33 neutralizing antibody. Maternal blood pressure, uterine artery resistance index, renal and placental oxidative stress, cNK, TH17, and TReg populations, various cytokines, and pre-proendothelin-1 levels were measured.
Results:
IL-33 signaling inhibition increased maternal blood pressure, uterine artery resistance, placental and renal oxidative stress. IL-33 signaling inhibition also increased placental cNK and TH17 and renal TH17 cells while decreasing placental TReg populations. IL-33 neutralization increased circulating cNK and TH17s and decreased circulating TRegs in addition to increasing pre-proendothelin-1 levels.
Conclusions:
Data presented in this study demonstrate a role for IL-33 signaling in controlling vascular function and maternal blood pressure during pregnancy possibly by mediating innate and adaptive immune inflammatory responses, identifying the IL-33 signaling pathway as a potential therapeutic target for managing preeclampsia.
