IL-33 Drives Inflammatory Changes and Extracellular Trap Formation in Eosinophils Involving Oxidised LDL and Complement Pathways.

Summary

Using primary human eosinophils with multi-omics and imaging, the authors show that IL-33 triggers an inflammatory program and extracellular trap formation (ETosis), with upregulation of OLR1, CD22, CD4 and ICAM-1. Oxidized LDL and complement fragments modulate eosinophil survival and adhesion, and IL-33-induced ETosis depends on NADPH oxidase, MAPK and PI3K pathways. Eosinophils from nasal polyps mirror IL-33–induced signatures, highlighting druggable pathways in eosinophilic airway disease.

Key Findings

• IL-33 and TNF-α induce an inflammatory gene signature in eosinophils, upregulating OLR1, CD22, CD4, and ICAM-1; CD22 upregulation was specific to IL-33.
• Eosinophils from nasal polyps exhibited gene-expression profiles similar to IL-33–stimulated cells, supporting in vivo relevance.
• Oxidized LDL and complement fragments (C3a, C5a) differentially prolonged eosinophil survival and altered adhesion molecule expression.
• IL-33 triggered eosinophil extracellular trap formation (ETosis) via NADPH oxidase, MAPK, and PI3K pathways.

Clinical Implications

Therapeutic strategies blocking IL-33/ST2, OLR1 (oxidized LDL receptor), or complement activation may reduce eosinophil ETosis and tissue damage in severe asthma and chronic rhinosinusitis with nasal polyps.

Limitations

• Predominantly in vitro/ex vivo human cell work without interventional in vivo models
• Sample sizes and donor heterogeneity are not detailed in the abstract, limiting generalizability

Future Directions

Test IL-33/ST2, OLR1, and complement-targeted interventions in animal models and early clinical trials; stratify eosinophilic airway disease by ETosis-prone molecular signatures.