Integrative Biosciences Center, Wayne State University, Detroit, MI, 48202, USA.
Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, 48202, USA.
Commun Biol. 2022 May 19;5(1):479. doi: 10.1038/s42003-022-03432-7.
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.
病理性视网膜新生血管（NV）是各种增生性视网膜病变的临床表现，而使用抗 VEGF 疗法治疗 NV 并不具有选择性，因为它也会损害正常的视网膜血管生长和功能。在这里，我们显示 IL-33 的基因缺失或 siRNA 介导的下调可减少氧诱导性视网膜病变（OIR）小鼠模型中的病理性 NV，而对正常视网膜修复没有影响。此外，我们的荧光激活细胞分选（FACS）数据显示，IL-33 的表达增加是在缺氧视网膜的内皮细胞（ECs）中，并且视网膜 ECs 中 IL-33 的条件性基因缺失可减少病理性 NV。使用人视网膜微血管内皮细胞（HRMVECs）的体外研究表明，IL-33 诱导出芽血管生成，并且需要 NFkappaB 介导的 Jagged1 表达和 Notch1 激活。我们的数据还表明，IL-33 通过与 BRCA1 相关蛋白 1（BAP1）和 HRMVECs 以及 OIR 小鼠模型中的 Numb 的相互作用，增强了 Notch1 细胞内结构域的去泛素化和稳定。
