The role of IL-33/ST2 signaling in female reproductive diseases

Ningzhen Zhang, 唐卯星, Mingwei Chen, Yuhua Shi
In: Frontiers in Cell and Developmental Biology · 2026 · vol. 14 · doi:10.3389/fcell.2026.1808099 · W7164576846
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⚙ AI-generated summary by claude@2026-06, 2026-06-14 ⓘ

This review integrates evidence to propose that IL-33/ST2 signaling is a context- and stage-dependent regulator of female reproduction, supporting physiological processes but potentially contributing to disease when disrupted.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-14 ⓘ

This paper is a review that synthesizes evidence on the IL-33/ST2 signaling axis in female reproductive tissues, integrating findings from animal and human studies across ovarian, endometrial, and pregnancy-related contexts, with particular attention to how hormonal status and the local microenvironment shape pathway activity. It argues that IL-33/ST2 is not uniformly pro- or anti-inflammatory; rather, properly timed and locally restricted signaling supports physiological processes such as ovarian tissue clearance, decidualization, embryo implantation, pregnancy maintenance, and repair, while disrupted regulation can contribute to chronic inflammation, fibrosis, immune imbalance, and reproductive dysfunction. The authors state that evidence is strongest mechanistically in endometriosis and recurrent miscarriage, whereas associations in primary ovarian insufficiency and polycystic ovary syndrome are more limited, and that dominant IL-33-producing cell types in the ovary remain controversial. Relevance to endometriosis: the review highlights strongest experimental and mechanistic links between IL-33/ST2 signaling and lesion inflammation and fibrosis in endometriosis, though its main focus is broadly integrating IL-33/ST2 roles across multiple reproductive diseases.

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Abstract

Female reproductive tissues repeatedly undergo controlled inflammation, immune adaptation, and tissue repair. Interleukin-33 (IL-33) and its receptor suppression of tumorigenicity 2 (ST2) sit at the center of these processes, but their roles in reproductive disease have often appeared contradictory. In this review, we integrate current evidence and propose that IL-33/ST2 signaling is not simply pro-inflammatory or anti-inflammatory. Instead, it functions as a context- and stage-dependent regulatory axis shaped by hormonal status, tissue niche, cellular targets, and disease microenvironment. Under physiological conditions, properly timed and locally restricted IL-33/ST2 activity supports ovarian tissue clearance, decidualization, embryo implantation, pregnancy maintenance, and repair. When this regulation is disrupted, the same pathway may contribute to chronic inflammation, fibrosis, immune imbalance, and reproductive dysfunction. Evidence is strongest in endometriosis and recurrent miscarriage, where experimental and mechanistic studies link IL-33/ST2 to lesion inflammation, fibrosis, ILC2 and macrophage responses, uterine receptivity, and maternal–fetal immune tolerance. In contrast, evidence in primary ovarian insufficiency and polycystic ovary syndrome remains mainly associative, involving altered serum or follicular-fluid IL-33/ST2-related markers and inflammatory-metabolic phenotypes. This evidence hierarchy argues against interpreting IL-33 as a static biomarker or a uniformly harmful mediator. Future studies should define the temporal dynamics, cellular sources, and tissue-specific targets of IL-33/ST2 signaling. Therapeutic development should prioritize precise, stage-specific, and cell-selective modulation rather than indiscriminate systemic blockade.

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