Resveratrol induces dynamic changes to the microglia transcriptome, inhibiting inflammatory pathways and protecting against microglia-mediated photoreceptor apoptosis

Wiedemann, Johanna; Rashid, Khalid; Langmann, Thomas

doi:10.1016/j.bbrc.2018.04.223

Cited by 18 publications

(13 citation statements)

References 35 publications

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“…In this study, LPS induced the phagocytosis of latex beads in BV-2 cells, consistent with previous findings [ 20 , 21 , 31 ]. We also found that I3C significantly reduced this phagocytic capacity.…”

Section: Discussionsupporting

confidence: 93%

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: 93%

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

Khan

Langmann

2020

J Neuroinflammation

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“…Moreover, the pro-inflammatory environment fostered by accumulating subretinal microglia can directly induce death of nearby photoreceptors (89). We have indeed demonstrated on several instances that conditioned medium from reactive human and murine microglial cells triggers caspase-mediated photoreceptor cell death (85, 90). These findings therefore strongly suggest that microglia reactivity is a driving force in photoreceptor degeneration and progression of retinal degenerative disorders.…”

Section: Microglia In the Diseased Retinamentioning

confidence: 89%

Microglia in Retinal Degeneration

2019

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The retina is a complex tissue with multiple cell layers that are highly ordered. Its sophisticated structure makes it especially sensitive to external or internal perturbations that exceed the homeostatic range. This necessitates the continuous surveillance of the retina for the detection of noxious stimuli. This task is mainly performed by microglia cells, the resident tissue macrophages which confer neuroprotection against transient pathophysiological insults. However, under sustained pathological stimuli, microglial inflammatory responses become dysregulated, often worsening disease pathology. In this review, we provide an overview of recent studies that depict microglial responses in diverse retinal pathologies that have degeneration and chronic immune reactions as key pathophysiological components. We also discuss innovative immunomodulatory therapy strategies that dampen the detrimental immunological responses to improve disease outcome.

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“…Consequently, research efforts have focused on the development of new pharmacological therapies to decrease photoreceptor loss, and not just on therapies to replace lost photoreceptors [23,115,116]. Many treatments such as trophic factors, anti-apoptotic drugs, antioxidant drugs, anti-inflammatory drugs, or gene therapies, among others, have been proposed to have beneficial effects on retinal degenerations [116,117,118,119,120,121]. For example, intravitreal (IVI) injections of anti-VEGF antibodies have been documented to slow the progression of some forms of AMD [122].…”

Section: Retinal Remodeling and Retinal Ganglion Cellsmentioning

confidence: 99%

Retinal Ganglion Cell Death as a Late Remodeling Effect of Photoreceptor Degeneration

García‐Ayuso

Pierdomenico

Vidal‐Sanz

et al. 2019

IJMS

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Inherited or acquired photoreceptor degenerations, one of the leading causes of irreversible blindness in the world, are a group of retinal disorders that initially affect rods and cones, situated in the outer retina. For many years it was assumed that these diseases did not spread to the inner retina. However, it is now known that photoreceptor loss leads to an unavoidable chain of events that cause neurovascular changes in the retina including migration of retinal pigment epithelium cells, formation of “subretinal vascular complexes”, vessel displacement, retinal ganglion cell (RGC) axonal strangulation by retinal vessels, axonal transport alteration and, ultimately, RGC death. These events are common to all photoreceptor degenerations regardless of the initial trigger and thus threaten the outcome of photoreceptor substitution as a therapeutic approach, because with a degenerating inner retina, the photoreceptor signal will not reach the brain. In conclusion, therapies should be applied early in the course of photoreceptor degeneration, before the remodeling process reaches the inner retina.

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Resveratrol induces dynamic changes to the microglia transcriptome, inhibiting inflammatory pathways and protecting against microglia-mediated photoreceptor apoptosis

Cited by 18 publications

References 35 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

Microglia in Retinal Degeneration

Retinal Ganglion Cell Death as a Late Remodeling Effect of Photoreceptor Degeneration

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