IL-33 enhances Jagged1 mediated NOTCH1 intracellular domain (NICD) deubiquitination and pathological angiogenesis in proliferative retinopathy

Abstract

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.

Vascular cell-adhesion molecule 1 (VCAM-1) regulates JunB-mediated IL-8/CXCL1 expression and pathological neovascularization

“…It is mainly expressed in epithelial cells, endothelial cells, and fibroblasts. Studies from our lab and others have shown that IL-33 induces angiogenesis in endothelial cells 20 , 21 . Contrary to it, few reports have also reported that IL-33 attenuates ocular angiogenesis 22 .…”

“…1g ). Our previous study showed that genetic deletion of IL-33 reduces retinal neovascularization in C57BL/6 mice 21 . A study reported significantly higher vitreous levels of vascular cell adhesion molecule (VCAM-1) in patients with proliferative diabetic retinopathy 27 .…”

“…Many studies including us have shown that IL-33 regulates NF-κB signaling pathway in endothelial cells 21 , and it has also been demonstrated that murine and human VCAM-1 promoter contain NF-κB DNA binding sequences 39 . We observed a significant augmentation in the expression of NF-κB signaling molecules and pharmacological inhibition of NF-κB signaling resulted in attenuation of IL-33-induced VCAM-1 expression in HRMVECs.…”

Dual Immune Regulatory Roles of Interleukin-33 in Pathological Conditions

“…A recent study showed that IL-33 induced by an oncogenic H-Ras mutant (H-Ras (G12V)) was mainly located in the nuclei of NIH-3T3 cells, and Ras (G12V)-induced cyclin D1 protein synthesis was significantly suppressed by IL-33 knockdown [ 49 ], suggesting a novel role for icIL-33 in cellular transformation. Genetic deletion of IL-33 in retinal endothelial cells reduced pathological retinal neovascularization [ 50 ]. IL-33 enhanced de-ubiquitination and stabilizes the notch1 intracellular domain via interactions with BRCA1-associated protein 1 and Numb in human retinal microvascular endothelial cells, as well as in a murine model of oxygen-induced retinopathy [ 50 ].…”

“…Genetic deletion of IL-33 in retinal endothelial cells reduced pathological retinal neovascularization [ 50 ]. IL-33 enhanced de-ubiquitination and stabilizes the notch1 intracellular domain via interactions with BRCA1-associated protein 1 and Numb in human retinal microvascular endothelial cells, as well as in a murine model of oxygen-induced retinopathy [ 50 ]. A recent study reported that icIL-33-mediated activation of the Smad signaling pathway in epithelial cells was essential for cancer development during chronic inflammation [ 51 ].…”