Journal
COMMUNICATIONS BIOLOGY
Volume 5, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42003-022-03432-7
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Funding
- National Institutes of Health [EY029709, EY014856]
- Research to Prevent Blindness
- NIH Center grant [P30 CA22453, R50 CA251068-01]
- [P30EY04068]
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This study discovered that genetic deletion or siRNA-mediated downregulation of IL-33 can reduce pathological neovascularization in a mouse model of oxygen-induced retinopathy without affecting normal retinal repair. It was also found that IL-33 induces angiogenesis through the NFkappaB-Jagged1-Notch1 signaling pathway. Additionally, IL-33 interacts with BRCA1-associated protein 1 (BAP1) and Numb to enhance the de-ubiquitination and stabilization of Notch1 intracellular domain.
Pathological retinal neovascularization (NV) is a clinical manifestation of various proliferative retinopathies, and treatment of NV using anti-VEGF therapies is not selective, as it also impairs normal retinal vascular growth and function. Here, we show that genetic deletion or siRNA-mediated downregulation of IL-33 reduces pathological NV in a murine model of oxygen-induced retinopathy (OIR) with no effect on the normal retinal repair. Furthermore, our fluorescent activated cell sorting (FACS) data reveals that the increase in IL-33 expression is in endothelial cells (ECs) of the hypoxic retina and conditional genetic deletion of IL-33 in retinal ECs reduces pathological NV. In vitro studies using human retinal microvascular endothelial cells (HRMVECs) show that IL-33 induces sprouting angiogenesis and requires NFkappaB-mediated Jagged1 expression and Notch1 activation. Our data also suggest that IL-33 enhances de-ubiquitination and stabilization of Notch1 intracellular domain via its interaction with BRCA1-associated protein 1 (BAP1) and Numb in HRMVECs and a murine model of OIR.
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