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Depletion of Retinal Dopaminergic Activity in a Mouse Model of Rod Dysfunction Exacerbates Experimental Autoimmune Uveoretinitis: A Role for the Gateway Reflex
A. Stofkova, M. Zloh, D. Andreanska, I. Fiserova, J. Kubovciak, J. Hejda, P. Kutilek, M. Murakami
Jazyk angličtina Země Švýcarsko
Typ dokumentu časopisecké články
Grantová podpora
GACR 18 11795Y
Grant Agency of the Czech Republic
PRIMUS/17/MED/7
Charles University
Progres Q35
Charles University
GAUK 378421
Charles University
260533/SVV/2021
Charles University
"PharmaBrain" CZ.02.1.01/0.0/0.0/16_025/0007444
European Regional Development Fund
NLK
Free Medical Journals
od 2000
Freely Accessible Science Journals
od 2000
PubMed Central
od 2007
Europe PubMed Central
od 2007
ProQuest Central
od 2000-03-01
Open Access Digital Library
od 2000-01-01
Open Access Digital Library
od 2007-01-01
Health & Medicine (ProQuest)
od 2000-03-01
ROAD: Directory of Open Access Scholarly Resources
od 2000
PubMed
35008877
DOI
10.3390/ijms23010453
Knihovny.cz E-zdroje
- MeSH
- buněčné linie MeSH
- dopamin metabolismus MeSH
- endoteliální buňky metabolismus patologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- NF-kappa B metabolismus MeSH
- retina metabolismus patologie MeSH
- transkripční faktor STAT3 metabolismus MeSH
- uveitida metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The gateway reflex is a mechanism by which neural inputs regulate chemokine expression at endothelial cell barriers, thereby establishing gateways for the invasion of autoreactive T cells into barrier-protected tissues. In this study, we hypothesized that rod photoreceptor dysfunction causes remodeling of retinal neural activity, which influences the blood-retinal barrier and the development of retinal inflammation. We evaluated this hypothesis using Gnat1rd17 mice, a model of night blindness with late-onset rod-cone dystrophy, and experimental autoimmune uveoretinitis (EAU). Retinal remodeling and its effect on EAU development were investigated by transcriptome profiling, target identification, and functional validation. We showed that Gnat1rd17 mice primarily underwent alterations in their retinal dopaminergic system, triggering the development of an exacerbated EAU, which was counteracted by dopamine replacement with L-DOPA administered either systemically or locally. Remarkably, dopamine acted on retinal endothelial cells to inhibit NF-κB and STAT3 activity and the expression of downstream target genes such as chemokines involved in T cell recruitment. These results suggest that rod-mediated dopamine release functions in a gateway reflex manner in the homeostatic control of immune cell entry into the retina, and the loss of retinal dopaminergic activity in conditions associated with rod dysfunction increases the susceptibility to autoimmune uveitis.
Citace poskytuje Crossref.org
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- $a The gateway reflex is a mechanism by which neural inputs regulate chemokine expression at endothelial cell barriers, thereby establishing gateways for the invasion of autoreactive T cells into barrier-protected tissues. In this study, we hypothesized that rod photoreceptor dysfunction causes remodeling of retinal neural activity, which influences the blood-retinal barrier and the development of retinal inflammation. We evaluated this hypothesis using Gnat1rd17 mice, a model of night blindness with late-onset rod-cone dystrophy, and experimental autoimmune uveoretinitis (EAU). Retinal remodeling and its effect on EAU development were investigated by transcriptome profiling, target identification, and functional validation. We showed that Gnat1rd17 mice primarily underwent alterations in their retinal dopaminergic system, triggering the development of an exacerbated EAU, which was counteracted by dopamine replacement with L-DOPA administered either systemically or locally. Remarkably, dopamine acted on retinal endothelial cells to inhibit NF-κB and STAT3 activity and the expression of downstream target genes such as chemokines involved in T cell recruitment. These results suggest that rod-mediated dopamine release functions in a gateway reflex manner in the homeostatic control of immune cell entry into the retina, and the loss of retinal dopaminergic activity in conditions associated with rod dysfunction increases the susceptibility to autoimmune uveitis.
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