Institute for Reproduction and Perinatal Research, Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas, KS, USA.
Department of Pediatrics, University of Kansas Medical Center, Kansas, KS, USA.
FASEB J. 2021 Feb;35(2):e21272. doi: 10.1096/fj.202001782RR.
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 estrogen-induced 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 wild-type rats treated with LPS did not differ significantly from pregnancy in vehicle-treated 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.
白细胞介素 33（IL33）信号在妊娠的建立和维持以及妊娠疾病中起作用。本项目的目的是评估 IL33 信号在大鼠妊娠中的作用。大鼠具有绒毛膜胎盘，具有深层子宫内滋养层侵袭的特征；这些特征也是人类胎盘的特征。我们使用 CRISPR/Cas9 基因组编辑生成并表征了 IL33 的基因敲除大鼠模型。缺乏 IL33 的大鼠对炎症刺激（葡聚糖 G-200）和雌激素诱导的子宫嗜酸性粒细胞增多的肺部反应存在缺陷。缺乏 IL33 的雌性大鼠可生育，其妊娠结局（妊娠时间和产仔数）与野生型大鼠相似。胎盘重量因 IL33 信号的破坏而受到影响。观察到野生型和 IL33 缺陷型妊娠对脂多糖（LPS）暴露的妊娠依赖性适应存在差异。用 LPS 处理的野生型大鼠的妊娠与用载体处理的野生型大鼠的妊娠没有显著差异。相比之下，LPS 处理降低了 IL33 缺陷型大鼠的胎儿存活率、胎儿和胎盘重量，并增加了胎儿生长受限。总之，已经建立了一种用于研究 IL33 信号的新型大鼠模型。IL33 信号参与胎盘发育的调节，并可防止 LPS 引起的胎儿和胎盘生长受限。
