IL-33/ST2 signalling in pediatric food allergy and eosinophilic gastrointestinal disorders: a systematic review of human and preclinical evidence

Abstract

Background Interleukin-33 (IL-33) is an epithelial-derived member of the IL-1 cytokine family that functions as an alarmin and signals through the ST2 receptor, upstream of type 2 inflammation. Together with thymic stromal lymphopoietin (TSLP) and IL-25, it constitutes an epithelial alarmin triad that orchestrates barrier-related immune responses. Despite substantial mechanistic data, the specific role of IL-33 as a biomarker and therapeutic target in pediatric food-related allergic disease remains insufficiently defined. Objective This systematic review aims to synthesize current evidence on serum and tissue IL-33 in pediatric IgE-mediated food allergy and eosinophilic gastrointestinal disorders (EGIDs), to delineate its association with disease severity, clinical phenotype and oral immunotherapy (OIT) outcomes, and to critically appraise the IL-33/ST2 axis as a candidate biomarker and therapeutic target within the broader epithelial alarmin network. Methods A systematic search of PubMed/MEDLINE, Web of Science, Scopus and the Cochrane Library (2010–2026) identified pediatric clinical studies quantifying IL-33 or IL-33/ST2 in food allergy or EGIDs, alongside murine and in vitro studies directly interrogating IL-33-dependent mechanisms in food allergy models. Eligible studies were screened and extracted according to predefined PICO criteria. Results Fourteen studies fulfilled the inclusion criteria (four pediatric clinical cohorts, ten direct preclinical murine or in vitro studies). Across murine models, keratinocyte-derived IL-33 consistently activated a skin-to-gut axis driving intestinal mast-cell expansion and IgE-independent food anaphylaxis, which was abrogated by genetic or pharmacologic ST2 blockade. In a small case-control study of nine children with eosinophilic gastroenteritis, serum IL-33 and TSLP were increased during active disease and declined after dietary elimination. In pediatric eosinophilic esophagitis, IL-33 was increased in tissue but not consistently in serum. Conversely, serum IL-33 demonstrated limited discriminatory value in IgE-mediated food allergy. Conclusions IL-33 emerges as a context-dependent yet non-redundant component of the epithelial alarmin circuitry in pediatric food-related allergic disease, as candidate biomarker of epithelial inflammation in pediatric EGIDs. However, current clinical evidence is limited and requires validation in larger prospective cohorts.