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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

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Title: Depletion of Retinal Dopaminergic Activity in a Mouse Model of Rod Dysfunction Exacerbates Experimental Autoimmune Uveoretinitis : A Role for the Gateway Reflex
Authors: Stofkova, Andrea Browse this author
Zloh, Miloslav Browse this author
Andreanska, Dominika Browse this author
Fiserova, Ivana Browse this author
Kubovciak, Jan Browse this author
Hejda, Jan Browse this author
Kutilek, Patrik Browse this author
Murakami, Masaaki Browse this author →KAKEN DB
Keywords: experimental autoimmune uveoretinitis
gateway reflex
dopamine
Gnat1
night blindness
rod-cone dystrophy
blood-retinal barrier
endothelial cells
NF-kappa B
STAT3
Issue Date: Jan-2022
Publisher: MDPI
Journal Title: International Journal of Molecular Sciences
Volume: 23
Issue: 1
Start Page: 453
Publisher DOI: 10.3390/ijms23010453
Abstract: 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 Gnat1(rd17) 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 Gnat1(rd17) 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-kappa B 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.
Type: article
URI: http://hdl.handle.net/2115/85512
Appears in Collections:遺伝子病制御研究所 (Institute for Genetic Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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