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 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.
Highlights
Because the outer nuclear layer (ONL) is composed of photoreceptors, these findings indicate that photoreceptor degeneration is not present in Gnat1rd17 mice at the age of experimental autoimmune uveoretinitis (EAU) induction
Given that systemic inflammation associated with elevated circulating C-reactive protein (CRP) levels can contribute to the development of retinal diseases, including uveitis and retinal degeneration [42,43], we examined whether EAU Gnat1rd17 mice exhibit a higher degree of systemic inflammation than EAU WT mice
We observed reduced DA receptor subtype D4 (DRD4)-ir in the retinal ONL and photoreceptor segment layer (PSL) in EAU Gnat1rd17 mice compared to EAU WT mice, whereas in healthy Gnat1rd17 mice compared to WT mice, we found decreased DRD4-ir in the inner nuclear layer (INL) and outer plexiform layer (OPL) (Figure 6b–e)
Summary
Autoimmune uveitis (AU) is an intraocular inflammatory disease that primarily affects adults in their most active and productive years [1]. Inflammation affecting the posterior segment of the eye is frequently associated with a substantial risk of ocular complications, permanent visual impairment, or even blindness [4,5]. RP refers to a heterogenic group of inherited retinal diseases characterized by a progressive degeneration of rod and cone photoreceptors. RP is described as rod–cone dystrophy due to primary degeneration of rods that precedes the cone loss. It is initially manifested by symptoms of night blindness, followed by peripheral visual field constriction and by loss of central vision in the most advanced stages [10]. Several studies have demonstrated that uveitis is not an uncommon condition in RP patients [11–14]
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