ABSTRACT Background IL‐33 levels are elevated in the airways of patients with eosinophilic diseases, and IL‐33 receptor expression on eosinophils is upregulated in type 2‐high environments. However, the role of IL‐33 in the regulation of human eosinophils remains unclear. Objective To elucidate the inflammatory effects of IL‐33 on the cellular function of human eosinophils. Methods Blood eosinophils were stimulated with IL‐33, TNF‐α, oxidised low‐density lipoprotein (oxLDL) and complement fragments (C3a and C5a). Multi‐omics analyses, including transcriptomics and proteomics, were performed. Extracellular trap formation (ETosis) was assessed by SYTOX nucleic acid staining and was visualised by immunofluorescence and transmission electron microscopy. Results Multi‐omics analyses revealed an IL‐33‐ and TNF‐α‐induced inflammatory gene signature characterised by the upregulation of cell surface markers (oxLDL receptor 1, CD22, CD4 and ICAM‐1) and inflammatory mediators (C3, CCL3/4 and IL1A/B). CD22 upregulation was specific to IL‐33 stimulation. Eosinophils derived from nasal polyps exhibited a gene expression profile similar to that of IL‐33‐stimulated eosinophils. Functional assays demonstrated that oxLDL and complement fragments differentially prolonged eosinophil survival and altered the expression of adhesion molecules. OxLDL‐ and complement fragment‐induced gene signatures were partly detected in eosinophils derived from nasal polyps. Furthermore, IL‐33 triggered ETosis via NADPH oxidase, mitogen‐activated protein kinase and phosphoinositide 3‐kinase pathways. Conclusions IL‐33, in conjunction with oxLDL and the complement cascade, induces inflammatory changes in eosinophils, promoting an ETosis‐prone phenotype. These pathways represent potential therapeutic targets in refractory eosinophilic diseases.
Matsuyama et al. (2026) studied this question.