Protective role of IL33 signaling in negative pregnancy outcomes associated with lipopolysaccharide exposure

Abstract

Interleukin 33 (IL33) signaling has been implicated in the establishment and maintenance of pregnancy and in pregnancy disorders. The goal of this project was to evaluate the role of IL33 signaling in rat pregnancy. The rat possesses hemochorial placentation with deep intrauterine trophoblast invasion; features also characteristic of human placentation. We generated and characterized a germline mutant rat model for IL33 using CRISPR/Cas9 genome editing. IL33 deficient rats exhibited deficits in lung responses to an inflammatory stimulus (Sephadex G-200) and to estrogeninduced uterine eosinophilia. Female rats deficient in IL33 were fertile and exhibited pregnancy outcomes (gestation length and litter size) similar to wild-type rats.Placental weight was adversely affected by the disruption of IL33 signaling. A difference in pregnancy-dependent adaptations to lipopolysaccharide (LPS) exposure was observed between wild-type and IL33 deficient pregnancies. Pregnancy in wildtype rats treated with LPS did not differ significantly from pregnancy in vehicletreated wild-type rats. In contrast, LPS treatment decreased fetal survival rate, fetal and placental weights, and increased fetal growth restriction in IL33 deficient rats.In summary, a new rat model for investigating IL33 signaling has been established. IL33 signaling participates in the regulation of placental development and protection against LPS-induced fetal and placental growth restriction.

Maternal IL-33 critically regulates tissue remodeling and type 2 immune responses in the uterus during early pregnancy in mice

“…Finally, although prior work had shown that IL-33 contributes to protection against LPS-induced complications and preterm labor at late gestation in mice and rats ( 17 , 18 ), we now demonstrate that IL-33 acts very early in pregnancy to critically regulate the tissue and vascular remodeling processes that establish the foundation for proper development and function of the placenta. This early role for IL-33 could impact, and possibly explain, some of the complications that arise at later stages of pregnancy in LPS-challenged rodents and in women with diverse pregnancy disorders.…”

“…Notably, both reduced and excessive IL-33 expression have been observed in distinct pregnancy disorders, suggesting that the magnitude and/or timing of IL-33 signaling may be a critical determinant of its specific biological effects on pregnancy outcomes ( 4 , 5 , 7 , 10 – 13 , 15 , 16 ). Nevertheless, few studies have addressed the functional requirement for IL-33 during pregnancy progression in vivo, and these have principally focused on very late gestation in lipopolysaccharide (LPS)-challenged mice ( 17 , 18 ). Collectively, these data suggest that properly regulated IL-33 signaling may be an important feature of mammalian pregnancy and highlight the need to better understand the contributions of IL-33 to the physiological and cellular processes that underlie a healthy pregnancy.…”

Conservation at the uterine–placental interface

“…Invasive trophoblast cells were conspicuous in their epithelial character (e.g., expression of cytokeratins: Krt7 , Krt8 , and Krt18 ) and expression of members of the expanded prolactin (PRL) gene family ( Prl7b1 , Prl5a1 , Prl4a1 , Prl2a1 , Prl5a2 , Prl2c1 , and Prl6a1 ) ( Dataset S1 ). To date, expression of cytokeratin and a subset of PRL gene family members have formed the basis of tracking invasive trophoblast cells within the rat uterine–placental interface ( 10 , 16 – 21 ).…”

Inherent maternal type 2 immunity: Consequences for maternal and offspring health

“…IL-33, an important early initiator of Type 2 immunity and its receptor ST2 are also enriched at the maternal fetal interface. Using IL-33-/-rats, this presence of IL-33 at the placental interface has been shown to also provide protection against LPS induced fetal restricted growth and failure of pregnancy [24]. Therefore, type 2 immunity at the maternalfoetal interface provides a significant level of protection against bacterial infection induced inflammation causing failure of pregnancy.…”