| First Author | Bisen S | Year | 2024 |
| Journal | Exp Mol Med | Volume | 56 |
| Issue | 8 | Pages | 1703-1716 |
| PubMed ID | 39085349 | Mgi Jnum | J:361335 |
| Mgi Id | MGI:7731371 | Doi | 10.1038/s12276-024-01279-y |
| Citation | Bisen S, et al. (2024) A neutrophil elastase-generated mature form of IL-33 is a potent regulator of endothelial cell activation and proliferative retinopathy. Exp Mol Med 56(8):1703-1716 |
| abstractText | Human interleukin-33 (IL-33) is a 270 amino acid protein that belongs to the IL-1 cytokine family and plays an important role in various inflammatory disorders. Neutrophil proteases (Cathepsin G and Elastase) and mast cell proteases (tryptase and chymase) regulate the activity of IL-33 by processing full-length IL-33 into its mature form. There is little evidence on the role of these mature forms of IL-33 in retinal endothelial cell signaling and pathological retinal angiogenesis. Here, we cloned, expressed, and purified the various mature forms of human IL-33 and then evaluated the effects of IL-33(95-270), IL-33(99-270), IL-33(109-270), and IL-33(112-270) on angiogenesis in human retinal microvascular endothelial cells (HRMVECs). We observed that IL-33(95-270), IL-33(99-270), IL-33(109-270), and IL-33(112-270) significantly induced HRMVEC migration, tube formation and sprouting angiogenesis. However, only IL-33(99-270) could induce HRMVEC proliferation. We used a murine model of oxygen-induced retinopathy (OIR) to assess the role of these mature forms of IL-33 in pathological retinal neovascularization. Our 3'-mRNA sequencing and signaling studies indicated that IL-33(99-270) and IL-33(109-270) were more potent at inducing endothelial cell activation and angiogenesis than the other mature forms. We found that genetic deletion of IL-33 significantly reduced OIR-induced retinal neovascularization in the mouse retina and that intraperitoneal administration of mature forms of IL-33, mainly IL-33(99-270) and IL-33(109-270), significantly restored ischemia-induced angiogenic sprouting and tuft formation in the hypoxic retinas of IL-33(-/-) mice. Thus, our study results suggest that blockade or inhibition of IL-33 cleavage by neutrophil proteases could help mitigate pathological angiogenesis in proliferative retinopathies. |
