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.

Loss of IL-33 in a murine model of retinopathy reduces pathological retinal neovascularization, which can be specified to the role of IL-33 in endothelial cells. IL-33 induces sprouting angiogenesis, and it requires NFkappaB-mediated Jagged 1 expression and Notch1 activation.

Details

Title
IL-33 enhances Jagged1 mediated NOTCH1 intracellular domain (NICD) deubiquitination and pathological angiogenesis in proliferative retinopathy
Author
Sharma, Deepti 1 ; Bisen Shivantika 1 ; Kaur Geetika 1 ; Van Buren Eric C 2 ; Rao, Gadiparthi N 3 ; Singh, Nikhlesh K 1   VIAFID ORCID Logo 

1  Wayne State University, Integrative Biosciences Center, Detroit, USA (GRID:grid.254444.7) (ISNI:0000 0001 1456 7807); Wayne State University School of Medicine, Department of Ophthalmology, Visual and Anatomical Sciences, Detroit, USA (GRID:grid.254444.7) (ISNI:0000 0001 1456 7807) 
2  Wayne State University School of Medicine, Department of Oncology, Detroit, USA (GRID:grid.254444.7) (ISNI:0000 0001 1456 7807) 
3  University of Tennessee Health Science Center, Department of Physiology, Memphis, USA (GRID:grid.267301.1) (ISNI:0000 0004 0386 9246) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
23993642
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s42003-022-03432-7
ProQuest document ID
2666718611
Copyright
© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.