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

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 bee...

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Autores principales: Hollingsworth, T.J., Hubbard, Meredith G., Levi, Hailey J., White, William, Wang, Xiangdi, Simpson, Raven, Jablonski, Monica M., Gross, Alecia K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393353/
https://www.ncbi.nlm.nih.gov/pubmed/34439829
http://dx.doi.org/10.3390/biom11081163
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author Hollingsworth, T.J.
Hubbard, Meredith G.
Levi, Hailey J.
White, William
Wang, Xiangdi
Simpson, Raven
Jablonski, Monica M.
Gross, Alecia K.
author_facet Hollingsworth, T.J.
Hubbard, Meredith G.
Levi, Hailey J.
White, William
Wang, Xiangdi
Simpson, Raven
Jablonski, Monica M.
Gross, Alecia K.
author_sort Hollingsworth, T.J.
collection PubMed
description 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.
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spelling pubmed-83933532021-08-28 Proinflammatory Pathways Are Activated in the Human Q344X Rhodopsin Knock-In Mouse Model of Retinitis Pigmentosa Hollingsworth, T.J. Hubbard, Meredith G. Levi, Hailey J. White, William Wang, Xiangdi Simpson, Raven Jablonski, Monica M. Gross, Alecia K. Biomolecules Article 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. MDPI 2021-08-06 /pmc/articles/PMC8393353/ /pubmed/34439829 http://dx.doi.org/10.3390/biom11081163 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hollingsworth, T.J.
Hubbard, Meredith G.
Levi, Hailey J.
White, William
Wang, Xiangdi
Simpson, Raven
Jablonski, Monica M.
Gross, Alecia K.
Proinflammatory Pathways Are Activated in the Human Q344X Rhodopsin Knock-In Mouse Model of Retinitis Pigmentosa
title Proinflammatory Pathways Are Activated in the Human Q344X Rhodopsin Knock-In Mouse Model of Retinitis Pigmentosa
title_full Proinflammatory Pathways Are Activated in the Human Q344X Rhodopsin Knock-In Mouse Model of Retinitis Pigmentosa
title_fullStr Proinflammatory Pathways Are Activated in the Human Q344X Rhodopsin Knock-In Mouse Model of Retinitis Pigmentosa
title_full_unstemmed Proinflammatory Pathways Are Activated in the Human Q344X Rhodopsin Knock-In Mouse Model of Retinitis Pigmentosa
title_short Proinflammatory Pathways Are Activated in the Human Q344X Rhodopsin Knock-In Mouse Model of Retinitis Pigmentosa
title_sort proinflammatory pathways are activated in the human q344x rhodopsin knock-in mouse model of retinitis pigmentosa
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393353/
https://www.ncbi.nlm.nih.gov/pubmed/34439829
http://dx.doi.org/10.3390/biom11081163
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