Fig. 4

The cascade of effects resulting from the release of IL-33 under the action of endothelial injury and other factors. Initially expressed within the nucleus, endogenous IL-33 expression is upregulated by endothelial injury and other stimuli, leading to the release of a significant amount of IL-33 outside the cell. Extracellular IL-33 binds to its receptor ST2, initiating downstream signaling events such as NF-κB and MAP kinase activation. Damaged endothelial cells promote the transition of neutrophils into pro-inflammatory and pro-coagulant phenotypes. Neutrophils release neutrophil extracellular traps (NETs), which further exacerbate neutrophil phenotypic transformation and enhance endothelial permeability through the MPO/H₂O₂-dependent activation of the TLR4/NF-κB signaling pathway. IL-33 also acts on CD8⁺ T cells and CD4⁺ T cells, leading to increased expression of IL-4, IL-5, and IL-13. Additionally, IL-33 stimulates mast cells, resulting in increased expression of IL-6, IL-1, IL-8, IL-13, CCL1, CXCL8, and TNF-α. Furthermore, IL-33 induces overexpression of MMP2 and MMP9 in macrophages