A novel AhR ligand, 2AI, protects the retina from environmental stress

Gutierrez, Mark A.; Davis, Sonnet S.; Rosko, Andrew; Nguyen, Steven; Mitchell, Kylie P.; Mateen, Samiha; Neves, Joana; Garcia, Thelma Y.; Mooney, Shaun; Perdew, Gary H.; Hubbard, Troy D.; Lamba, Deepak A.; Ramanathan, Arvind

doi:10.1038/srep29025

Cited by 25 publications

(27 citation statements)

References 51 publications

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“…We also noticed that I3C upregulated NQO1 and HMOX1 protein levels in the retina of light-treated animals. Consistent with our data, 2AI, a synthetic AhR ligand enhanced the antioxidant battery of genes in the retina [ 15 ]. AhR is obviously necessary for normal immune physiology as AhR-deficient mice display a highly inflammatory phenotype with high levels of oxidative stress in the retina [ 47 , 48 ].…”

Section: Discussionsupporting

confidence: 92%

“…Recent studies showed that AhR is important for the maintenance of photoreceptor and RPE homeostasis [ 13 , 15 ]. To our knowledge, we here show for the first time that AhR also regulates microglia homeostasis in the degenerating retina and that its natural ligand I3C protects from acute light damage, a model system that mimics certain aspects of human retinal degeneration.…”

Section: Discussionmentioning

confidence: 99%

“…AhR −/− mice also showed larger lesions in laser-induced choroidal neovascularization that mimics the wet form of AMD [ 14 ]. Furthermore, 2,2′-aminophenyl indole (2AI), a synthetic ligand of AhR could protect the RPE and retina from environmental stress [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Indole-3-carbinol regulates microglia homeostasis and protects the retina from degeneration

Khan

Langmann

2020

J Neuroinflammation

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Background Retinal degenerative diseases significantly contribute to visual impairment and blindness. Microglia reactivity is a hallmark of neurodegenerative diseases including retinal cell death and immunomodulation emerges as a therapeutic option. Indole-3-carbinol (I3C) is a natural ligand of aryl hydrocarbon receptor (AhR), with potent immunomodulatory properties. Here, we hypothesized that I3C may inhibit microglia reactivity and exert neuroprotective effects in the light-damaged murine retina mimicking important immunological aspects of retinal degeneration. Methods BV-2 microglia were treated in vitro with I3C followed by lipopolysaccharide (LPS) stimulation to analyze pro-inflammatory and anti-oxidant responses by quantitative real-time PCR (qRT-PCR) and Western blots. Nitric oxide (NO) secretion, caspase 3/7 levels, phagocytosis rates, migration, and morphology were analyzed in control and AhR knockdown cells. I3C or vehicle was systemically applied to light-treated BALB/cJ mice as an experimental model of retinal degeneration. Pro-inflammatory and anti-oxidant responses in the retina were examined by qRT-PCR, ELISA, and Western blots. Immunohistochemical staining of retinal flat mounts and cryosections were performed. The retinal thickness and structure were evaluated by in vivo imaging using spectral domain-optical coherence tomography (SD-OCT). Results The in vitro data showed that I3C potently diminished LPS-induced pro-inflammatory gene expression of I-NOS, IL-1ß, NLRP3, IL-6, and CCL2 and induced anti-oxidants gene levels of NQO1, HMOX1, and CAT1 in BV-2 cells. I3C also reduced LPS-induced NO secretion, phagocytosis, and migration as important functional microglia parameters. siRNA-mediated knockdown of AhR partially prevented the previously observed gene regulatory events. The in vivo experiments revealed that I3C treatment diminished light-damage induced I-NOS, IL-1ß, NLRP3, IL-6, and CCL2 transcripts and also reduced CCL2, I-NOS, IL-1ß, p-NFkBp65 protein levels in mice. Moreover, I3C increased anti-oxidant NQO1 and HMOX1 protein levels in light-exposed retinas. Finally, I3C therapy prevented the accumulation of amoeboid microglia in the subretinal space and protected from retinal degeneration. Conclusions The AhR ligand I3C potently counter-acts microgliosis and light-induced retinal damage, highlighting a potential treatment concept for retinal degeneration.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Indole-3-carbinol regulates microglia homeostasis and protects the retina from degeneration

Khan

Langmann

2020

J Neuroinflammation

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“…Kim SY and colleagues also observed an atrophy of these cells, together with a sub-retinal accumulation of microglial cells [ 175 ]. In wild-type mice, the use of a synthetic AhR ligand protects the degeneration of RPE by alteration of lipid metabolism [ 176 ]. As stated before, the AhR is also expressed in the RGC of the mouse retina, and the dysregulation of such cells in AhR KO mice could be also a key event in the occurrence of the spontaneous pendular horizontal nystagmus.…”

Section: The Physiological Functions Of the Ahr In The Central Nermentioning

confidence: 99%

The Aryl Hydrocarbon Receptor and the Nervous System

Juricek

Coumoul

2018

IJMS

111

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The aryl hydrocarbon receptor (or AhR) is a cytoplasmic receptor of pollutants. It translocates into the nucleus upon binding to its ligands, and forms a heterodimer with ARNT (AhR nuclear translocator). The heterodimer is a transcription factor, which regulates the transcription of xenobiotic metabolizing enzymes. Expressed in many cells in vertebrates, it is mostly present in neuronal cell types in invertebrates, where it regulates dendritic morphology or feeding behavior. Surprisingly, few investigations have been conducted to unravel the function of the AhR in the central or peripheral nervous systems of vertebrates. In this review, we will present how the AhR regulates neural functions in both invertebrates and vertebrates as deduced mainly from the effects of xenobiotics. We will introduce some of the molecular mechanisms triggered by the well-known AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which impact on neuronal proliferation, differentiation, and survival. Finally, we will point out the common features found in mice that are exposed to pollutants, and in AhR knockout mice.

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“… 25 Cyt-b5 is required for synthesis of fatty acids including palmitoleic acid (16:1Δ), which has been shown to protect the mouse retina from light-induced damage. 26 However, overexpression of Cyt-b5 did not alter the ratio of polyunsaturated fatty acids, or increase relative levels of palmitoleic acid, in the eye (Supplementary Fig. 3 ).…”

Section: Resultsmentioning

confidence: 91%

Cytochrome b5 protects photoreceptors from light stress-induced lipid peroxidation and retinal degeneration

et al. 2017

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Lipid peroxides are generated by oxidative stress in cells, and contribute to ageing and neurodegenerative disease. The eye is at special risk for lipid peroxidation because photoreceptors possess amplified sensory membranes rich in peroxidation-susceptible polyunsaturated fatty acids. Light-induced lipid peroxidation in the retina contributes to retinal degeneration, and lipid peroxidation has been implicated in the progression of age-associated ocular diseases such as age-related macular degeneration (AMD). Here, we show that exposing Drosophila melanogaster to strong blue light induces oxidative stress including lipid peroxidation that results in retinal degeneration. Surprisingly, very young flies are resilient to this acute light stress, suggesting they possess endogenous neuroprotective mechanisms. While lipophilic antioxidants partially suppressed blue light-induced retinal degeneration in older flies, we find that overexpression of cytochrome b5 (Cyt-b5) completely suppressed both blue light-induced lipid peroxidation and retinal degeneration. Our data identify Cyt-b5 as a neuroprotective factor that targets light-induced oxidative damage, particularly lipid peroxidation. Cyt-b5 may function via supporting antioxidant recycling, thereby providing a strategy to prevent oxidative stress in ageing photoreceptors that would be synergistic with dietary antioxidant supplementation.

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A novel AhR ligand, 2AI, protects the retina from environmental stress

Cited by 25 publications

References 51 publications

Indole-3-carbinol regulates microglia homeostasis and protects the retina from degeneration

Indole-3-carbinol regulates microglia homeostasis and protects the retina from degeneration

The Aryl Hydrocarbon Receptor and the Nervous System

Cytochrome b5 protects photoreceptors from light stress-induced lipid peroxidation and retinal degeneration

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