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Proinflammatory Pathways Are Activated in the Human Q344X Rhodopsin Knock-In Mouse Model of Retinitis Pigmentosa

Authors :
T.J. Hollingsworth
Meredith G. Hubbard
Hailey J. Levi
William White
Xiangdi Wang
Raven Simpson
Monica M. Jablonski
Alecia K. Gross
Source :
Biomolecules, Vol 11, Iss 8, p 1163 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

Retinitis pigmentosa (RP) is a hereditary disease of the retina that results in complete blindness. Currently, there are very few treatments for the disease and those that exist work only for the recessively inherited forms. To better understand the pathogenesis of RP, multiple mouse models have been generated bearing mutations found in human patients including the human Q344X rhodopsin knock-in mouse. In recent years, the immune system was shown to play an increasingly important role in RP degeneration. By way of electroretinography, optical coherence tomography, funduscopy, fluorescein angiography, and fluorescent immunohistochemistry, we show degenerative and vascular phenotypes, microglial activation, photoreceptor phagocytosis, and upregulation of proinflammatory pathway proteins in the retinas of the human Q344X rhodopsin knock-in mouse. We also show that an FDA-approved pharmacological agent indicated for the treatment of rheumatoid arthritis is able to halt activation of pro-inflammatory signaling in cultured retinal cells, setting the stage for pre-clinical trials using these mice to inhibit proinflammatory signaling in an attempt to preserve vision. We conclude from this work that pro- and autoinflammatory upregulation likely act to enhance the progression of the degenerative phenotype of rhodopsin Q344X-mediated RP and that inhibition of these pathways may lead to longer-lasting vision in not only the Q344X rhodopsin knock-in mice, but humans as well.

Details

Language :
English
ISSN :
11081163 and 2218273X
Volume :
11
Issue :
8
Database :
Directory of Open Access Journals
Journal :
Biomolecules
Publication Type :
Academic Journal
Accession number :
edsdoj.51222d457ee84673bc4a2aceedf7499d
Document Type :
article
Full Text :
https://doi.org/10.3390/biom11081163