Interleukin-33 at the maternal-fetal interface: From immune tolerance to obstetric syndromes

Successful viviparous reproduction depends on a finely tuned state of maternal-fetal immune tolerance. Among the mediators that shape this balance, the alarmin cytokine interleukin-33 (IL-33) has drawn growing attention as a key regulatory checkpoint. Here, we bring together recent findings to interpret IL-33 function through a "Two-Wave" framework that helps reconcile its seemingly opposing roles in pregnancy. In early gestation, a controlled, spatially confined release of IL-33 appears essential for processes such as decidualization, spiral artery remodeling, and the establishment of a Type 2-biased immune environment. These effects are largely mediated through group 2 innate lymphoid cells, regulatory T cells, and M2 macrophages, which collectively sustain a tolerogenic interface. Later in pregnancy, however, an abrupt or excessive surge of IL-33-often in response to infection or tissue injury-can provoke intense inflammation. Such is now recognized as a shared pathological feature in major obstetric syndromes. In preeclampsia, excess sST2 neutralizes IL-33 activity, creating a state of functional deficiency, whereas in preterm birth, IL-33 released from fetal membranes may act as a trigger for premature labor. Given its pivotal position at the intersection of immune tolerance and inflammation, the IL-33/ST2 pathway offers both mechanistic insight and promising opportunities for biomarker development and targeted immunotherapy in complicated pregnancies.