Paraquat-Induced Retinal Degeneration Is Exaggerated in CX3CR1-Deficient Mice and Is Associated with Increased Retinal Inflammation

Chen, Mei; Luo, Chang; Peñalva, Rosana; Xu, Heping

doi:10.1167/iovs.12-10888

Cited by 25 publications

(28 citation statements)

References 39 publications

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“…The neuronal cell bodies unaffected by Met treatment were most likely not expressing the Ntr transgene. Our TEM analysis revealed signs of degeneration in the neuronal cell bodies of Met-treated Ntr larvae consistent with previous reports that showed neuronal membrane disruption in a toxin-induced axon degeneration mouse model, and with those from a drosophila mutant with disrupted axonal transport leading to axon degeneration [58], [59]. Thus, the results from these TEM studies support the observations made at a macro level with epifluorescence microscopy.…”

Section: Resultssupporting

confidence: 91%

Peripheral Glia Have a Pivotal Role in the Initial Response to Axon Degeneration of Peripheral Sensory Neurons in Zebrafish

Pope

Voigt

2014

PLoS ONE

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Axon degeneration is a feature of many peripheral neuropathies. Understanding the organismal response to this degeneration may aid in identifying new therapeutic targets for treatment. Using a transgenic zebrafish line expressing a bacterial nitroreductase (Ntr)/mCherry fusion protein in the peripheral sensory neurons of the V, VII, IX, and X cranial nerves, we were able to induce and visualize the pathology of axon degeneration in vivo. Exposure of 4 days post fertilization Ntr larvae to the prodrug metronidazole (Met), which Ntr metabolizes into cytotoxic metabolites, resulted in dose-dependent cell death and axon degeneration. This was limited to the Ntr-expressing sensory neurons, as neighboring glia and motor axons were unaffected. Cell death was rapid, becoming apparent 3–4 hours after Met treatment, and was followed by phagocytosis of soma and axon debris by cells within the nerves and ganglia beginning at 4–5 hours of exposure. Although neutrophils appear to be activated in response to the degenerating neurons, they did not accumulate at the sites of degeneration. In contrast, macrophages were found to be attracted to the sites of the degenerating axons, where they phagocytosed debris. We demonstrated that peripheral glia are critical for both the phagocytosis and inflammatory response to degenerating neurons: mutants that lack all peripheral glia (foxD3−/−; Ntr) exhibit a much reduced reaction to axonal degeneration, resulting in a dramatic decrease in the clearance of debris, and impaired macrophage recruitment. Overall, these results show that this zebrafish model of peripheral sensory axon degeneration exhibits many aspects common to peripheral neuropathies and that peripheral glia play an important role in the initial response to this process.

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Section: Resultssupporting

confidence: 91%

Peripheral Glia Have a Pivotal Role in the Initial Response to Axon Degeneration of Peripheral Sensory Neurons in Zebrafish

Pope

Voigt

2014

PLoS ONE

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“…A commonly used molecule to mimic the effects of oxidative stress in the CNS is paraquat, 1,1′-Dimethyl-4,4′-bipyridinium dichloride, which generates oxygen free radicals through redox cycling and NADPH oxidase regulation (Corasaniti et al, 1998; McCormack et al, 2005; Cingolani et al, 2006; Chen et al, 2013). In this study, we used paraquat (PQ) to induce acute oxidative stress in the retina.…”

Section: Resultsmentioning

confidence: 99%

“…A recent study demonstrated that inflammatory cytokines protect against oxidative stress induced degeneration of the RPE (Chen et al, 2013; Juel et al, 2013). TLR3 signaling within astrocytes leads to secretion of neuroprotective mediators and promotes tissue repair responses (Bsibsi et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

A novel protective role for the innate immunity Toll-Like Receptor 3 (TLR3) in the retina via Stat3

Patel

Hackam

2014

Molecular and Cellular Neuroscience

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The innate immune system and inflammatory pathways play key roles in numerous diseases of the central nervous system (CNS). Recent evidence indicates that innate immunity induces both pathogenesis and protection during neuronal injury. To test the possibility that the conflicting roles of innate immunity in the CNS depends on the cellular environment in which innate immunity is stimulated, we analyzed the effect of toll-like receptor 3 (TLR3) activation on neuronal survival in the presence and absence of oxidative injury in a mouse model system. We demonstrated that activation of TLR3 by the double stranded RNA activator, Poly (I:C), during paraquat induced oxidative stress, significantly protected mouse photoreceptors, as measured by increased retinal structure, function, and improved visual acuity. In contrast, TLR3 activation without concurrent oxidative injury was neurotoxic. The neurotoxic and protective effects of Poly (I:C) stimulation were absent in TLR3 knockout animals, which indicates that protection by Poly (I:C) is dependent on the TLR3 signaling pathway. Furthermore, we identified the pro-survival transcription factor Stat3 as a necessary mechanism for protection. Knockdown of Stat3 using lentivirally delivered shRNA abolished the protective effects of TLR3 signaling in the retina during oxidative stress. Therefore, TLR3 activation in the context of oxidative stress triggers protective instead of pathogenic signaling, suggesting that TLR3 is a potential therapeutic target for neurodegeneration where oxidative stress is a significant contributor.

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“…High Cx3Cr1 expression has been associated with a functionally distinct class of monocytes with immune patrolling activity and with a molecular profile of macrophage differentiation resembling alternative activation (18, 19). Loss of Cx3Cr1 results in retinal degeneration in response to several stimuli and is associated with pro-inflammatory activation of immune cells (9, 14, 59). Thus we hypothesized that loss of Cx3Cr1 could be an effective way to impair MANF-induced alternative activation.…”

Section: Manf-dependent Modulation Of Immune Cell Phenotypes Mediatesmentioning

confidence: 99%

Immune modulation by MANF promotes tissue repair and regenerative success in the retina

Neves

Zhu

Sousa‐Victor

et al. 2016

Science

200

215

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Regenerative therapies are limited by unfavorable environments in aging and diseased tissues. A promising strategy to improve success is to balance inflammatory and anti-inflammatory signals and enhance endogenous tissue repair mechanisms. Here, we identified a conserved immune modulatory mechanism that governs the interaction between damaged retinal cells and immune cells to promote tissue repair. In damaged retina of flies and mice, Platelet-Derived Growth Factor (PDGF)-like signaling induced Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) in innate immune cells. MANF promoted alternative activation of innate immune cells, enhanced neuroprotection and tissue repair, and improved the success of photoreceptor replacement therapies. Thus, immune modulation is required during tissue repair and regeneration. This approach may improve the efficacy of stem-cell based regenerative therapies.

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Paraquat-Induced Retinal Degeneration Is Exaggerated in CX3CR1-Deficient Mice and Is Associated with Increased Retinal Inflammation

Cited by 25 publications

References 39 publications

Peripheral Glia Have a Pivotal Role in the Initial Response to Axon Degeneration of Peripheral Sensory Neurons in Zebrafish

Peripheral Glia Have a Pivotal Role in the Initial Response to Axon Degeneration of Peripheral Sensory Neurons in Zebrafish

A novel protective role for the innate immunity Toll-Like Receptor 3 (TLR3) in the retina via Stat3

Immune modulation by MANF promotes tissue repair and regenerative success in the retina

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