Depletion of Retinal Dopaminergic Activity in a Mouse Model of Rod Dysfunction Exacerbates Experimental Autoimmune Uveoretinitis: A Role for the Gateway Reflex

0555979 - ÚMG 2023 RIV CH eng J - Článek v odborném periodiku
Štofková, A. - Zloh, M. - Andreanska, D. - Fišerová, I. - Kubovčiak, Jan - Hejda, J. - Kutílek, P. - Murakami, M.
Depletion of Retinal Dopaminergic Activity in a Mouse Model of Rod Dysfunction Exacerbates Experimental Autoimmune Uveoretinitis: A Role for the Gateway Reflex.
International Journal of Molecular Sciences. Roč. 23, č. 1 (2022), č. článku 453. E-ISSN 1422-0067
Institucionální podpora: RVO:68378050
Klíčová slova: experimental autoimmune uveoretinitis * gateway reflex * dopamine * Gnat1 * night blindness * rod-cone dystrophy * blood-retinal barrier * endothelial cells * NF-kappa B * stat3
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 5.6, rok: 2022
Způsob publikování: Open access
https://www.mdpi.com/1422-0067/23/1/453

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.
Trvalý link: http://hdl.handle.net/11104/0330892