Universität zu Köln

Shi, Xin ORCID: 0000-0002-6649-4045, Li, Panpan ORCID: 0000-0001-5777-0899, Herb, Marc ORCID: 0000-0002-7533-0288, Liu, Hanhan ORCID: 0000-0003-0204-1087, Wang, Maoren, Wang, Xiaosha ORCID: 0009-0003-8044-3951, Feng, Yuan, van Beers, Tim ORCID: 0000-0002-5645-2853, Xia, Ning, Li, Huige and Prokosch, Verena ORCID: 0000-0002-5318-0637 (2024). Pathological high intraocular pressure induces glial cell reactive proliferation contributing to neuroinflammation of the blood-retinal barrier via the NOX2/ET-1 axis-controlled ERK1/2 pathway. Journal of Neuroinflammation, 21 (1). pp. 1-23. Springer Nature. ISSN 1742-2094

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Abstract

[Artikel-Nr.: 105] Background: NADPH oxidase (NOX), a primary source of endothelial reactive oxygen species (ROS), is considered a key event in disrupting the integrity of the blood-retinal barrier. Abnormalities in neurovascular-coupled immune signaling herald the loss of ganglion cells in glaucoma. Persistent microglia-driven inflammation and cellular innate immune system dysregulation often lead to deteriorating retinal degeneration. However, the crosstalk between NOX and the retinal immune environment remains unresolved. Here, we investigate the interaction between oxidative stress and neuroinflammation in glaucoma by genetic defects of NOX2 or its regulation via gp91ds-tat. Methods: Ex vivo cultures of retinal explants from wildtype C57BL/6J and Nox2 −/− mice were subjected to normal and high hydrostatic pressure (Pressure 60 mmHg) for 24 h. In vivo, high intraocular pressure (H-IOP) was induced in C57BL/6J mice for two weeks. Both Pressure 60 mmHg retinas and H-IOP mice were treated with either gp91ds-tat (a NOX2-specific inhibitor). Proteomic analysis was performed on control, H-IOP, and treatment with gp91ds-tat retinas to identify differentially expressed proteins (DEPs). The study also evaluated various glaucoma phenotypes, including IOP, retinal ganglion cell (RGC) functionality, and optic nerve (ON) degeneration. The superoxide (O 2 - ) levels assay, blood-retinal barrier degradation, gliosis, neuroinflammation, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative PCR were performed in this study. Results: We found that NOX2-specific deletion or activity inhibition effectively attenuated retinal oxidative stress, immune dysregulation, the internal blood-retinal barrier (iBRB) injury, neurovascular unit (NVU) dysfunction, RGC loss, and ON axonal degeneration following H-IOP. Mechanistically, we unveiled for the first time that NOX2-dependent ROS-driven pro-inflammatory signaling, where NOX2/ROS induces endothelium-derived endothelin-1 (ET-1) overexpression, which activates the ERK1/2 signaling pathway and mediates the shift of microglia activation to a pro-inflammatory M1 phenotype, thereby triggering a neuroinflammatory outburst. Conclusions: Collectively, we demonstrate for the first time that NOX2 deletion or gp91ds-tat inhibition attenuates iBRB injury and NVU dysfunction to rescue glaucomatous RGC loss and ON axon degeneration, which is associated with inhibition of the ET-1/ERK1/2-transduced shift of microglial cell activation toward a pro-inflammatory M1 phenotype, highlighting NOX2 as a potential target for novel neuroprotective therapies in glaucoma management.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Shi, Xin UNSPECIFIED https://orcid.org/0000-0002-6649-4045 UNSPECIFIED Li, Panpan UNSPECIFIED https://orcid.org/0000-0001-5777-0899 UNSPECIFIED Herb, Marc UNSPECIFIED https://orcid.org/0000-0002-7533-0288 UNSPECIFIED Liu, Hanhan UNSPECIFIED https://orcid.org/0000-0003-0204-1087 UNSPECIFIED Wang, Maoren UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Xiaosha UNSPECIFIED https://orcid.org/0009-0003-8044-3951 UNSPECIFIED Feng, Yuan UNSPECIFIED UNSPECIFIED UNSPECIFIED van Beers, Tim UNSPECIFIED https://orcid.org/0000-0002-5645-2853 UNSPECIFIED Xia, Ning UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Huige UNSPECIFIED UNSPECIFIED UNSPECIFIED Prokosch, Verena UNSPECIFIED https://orcid.org/0000-0002-5318-0637 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-815396
Identification Number:	10.1186/s12974-024-03075-x
Journal or Publication Title:	Journal of Neuroinflammation
Volume:	21
Number:	1
Page Range:	pp. 1-23
Number of Pages:	23
Date:	22 April 2024
Publisher:	Springer Nature
ISSN:	1742-2094
Language:	English
Faculty:	Faculty of Medicine
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Medicine > Anatomie > Institut I für Anatomie Faculty of Medicine > Augenheilkunde > Klinik und Poliklinik für Allgemeine Augenheilkunde Faculty of Medicine > Medizinische Mikrobiologie, Immunologie und Hygiene > Institut für Medizinische Mikrobiologie, Immunologie und Hygiene
Subjects:	Life sciences Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language NADPH oxidase 2 ; Deletion ; Pharmacological inhibition ; Oxidative stress ; Neurodegeneration ; Neuroinflammation ; Vascular dysfunction ; Glaucoma English
['eprint_fieldname_oa_funders' not defined]:	verena.prokosch@uk-koeln.de
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81539