June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
NADPH Oxidase-dependent ZO1 phosphorylation regulates IL-33-induced inner Blood-Retinal Barrier (iBRB) disruption in proliferative retinopathies.
Author Affiliations & Notes
  • Geetika Kaur
    Ophthalmology Visual and Anatomical Sciences, Wayne State University, Detroit, Michigan, United States
  • Shivantika Bisen
    Ophthalmology Visual and Anatomical Sciences, Wayne State University, Detroit, Michigan, United States
  • Nikhlesh Kumar Singh
    Ophthalmology Visual and Anatomical Sciences, Wayne State University, Detroit, Michigan, United States
  • Footnotes
    Commercial Relationships   Geetika Kaur None; Shivantika Bisen None; Nikhlesh Kumar Singh None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1794. doi:
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      Geetika Kaur, Shivantika Bisen, Nikhlesh Kumar Singh; NADPH Oxidase-dependent ZO1 phosphorylation regulates IL-33-induced inner Blood-Retinal Barrier (iBRB) disruption in proliferative retinopathies.. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1794.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Angiogenesis, neovascularization, and vascular remodeling are highly dynamic processes where endothelial cell-cell adhesion within the vessel wall controls various physiological processes, such as growth, integrity, and barrier function. The tight junction complex contributes to the integrity of the inner blood-retinal barrier (BRB). However, the structure and function of tight junctions in proliferative retinopathies still need to be determined. Additionally, it is unknown how IL33 signaling controls BRB integrity.

Methods : We attempted to comprehend the relevance of IL-33 on endothelial barrier breakdown, which results in aberrant angiogenesis and higher vascular permeability. We used a murine model of oxygen-induced retinopathy (OIR) and human retinal microvascular endothelial cells (HRMVECs) as a model to study our hypothesis.

Results : Using IL-33 knockout mouse model, we have demonstrated that genetic deletion of IL-33 decreased OIR-induced vascular leakage and retinal neovascularization. Next, using HRMVECs as a model, we identified the mechanisms through which IL-33 regulates retinal endothelial cell barrier permeability. The electric cell-substrate impedance sensing (ECIS) analysis and the FITC-dextran permeability assay showed that IL-33 stimulates endothelial dysfunction in HRMVECs. The tight junctions (TJs) proteins are the essential regulators of the selective diffusion of molecules from the blood to the retina and maintain retinal homeostasis. Therefore, we looked for the involvement of tight junctional proteins in IL-33-mediated endothelial dysfunction. We observed that IL-33 does not affect steady-state levels of tight junction proteins, such as zonula occludins 1 (ZO1), ZO2, Claudin1, Claudin5, Claudin 19, Occludin, and JAM-A. In addition, we also failed to observe any effect of IL-33 on the tyrosine phosphorylation of tight junction proteins. We observed that IL-33 induces the Ser/Thr phosphorylation of ZO1 in HRMVECs with little or no effect on other tight junction proteins. In HRMVECs and the OIR model, IL-33 via NADPH oxidase-mediated ZO1 Ser/Thr phosphorylation regulates retinal endothelial cell permeability and iBRB integrity.

Conclusions : We conclude that IL-33-regulated NADPH oxidase-dependent ZO1 phosphorylation regulates iBRB integrity and retinal neovascularization.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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