Axon injury signaling and compartmentalized injury response in glaucoma

Syc-Mazurek, Stephanie B; Libby, Richard T.

doi:10.1016/j.preteyeres.2019.07.002

Cited by 69 publications

(51 citation statements)

References 258 publications

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“…Our findings indicated that the inhibition of astroglia-driven neuroinflammation can protect both axons and somas of RGCs in experimental glaucoma. Indeed, besides the RGC soma injury evident in glaucoma, glial NF-κB-mediated inflammation has been implicated in the self-destruction of injured axons [ 13 , 38 ], which is relevant to glaucomatous axon pathology [ 5 ]. Evidently, NF-κB-regulated pro-inflammatory cytokines, such as TNF-α [ 9 , 39 ] or FasL [ 40 ] secreted by reactive astrocytes, can induce RGC apoptosis and axon degeneration.…”

Section: Discussionmentioning

confidence: 99%

“…Besides innate immunity, prolonged responses of these resident immunocompetent cells may also stimulate adaptive immunity, and autoreactive T cells, autoantibodies, and complement components may become potent stimuli to harm RGCs during glaucomatous neurodegeneration [ 1 – 4 ]. While growing information points to independent molecular processes for glaucomatous degeneration of RGCs at different subcellular regions [ 5 ], glia-driven neuroinflammation appears to promote neuron injury throughout the visual pathway. Viewing the big picture of glaucoma and respecting the diverse roles of glia (which are normally neurosupportive versus neurodestructive under glaucoma-related stress), these critical cells constitute a promising treatment target for the modulation of neurodegenerative inflammation at different injury sites from the retina to the brain.…”

Section: Introductionmentioning

confidence: 99%

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Transgenic inhibition of astroglial NF-κB restrains the neuroinflammatory and neurodegenerative outcomes of experimental mouse glaucoma

Yang

Zeng

Barış

et al. 2020

J Neuroinflammation

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Background: Glia-driven neuroinflammation promotes neuron injury in glaucoma that is a chronic neurodegenerative disease of the optic nerve and a leading cause of irreversible blindness. Although therapeutic modulation of neuroinflammation is increasingly viewed as a logical strategy to avoid inflammatory neurotoxicity in glaucoma, current understanding of the molecular regulation of neuroinflammation is incomplete, and the molecular targets for immunomodulation remains unknown. Growing datasets pointed to nuclear factor-kappaB (NF-κB), a key transcriptional activator of inflammation, which was identified to be most affected in glaucomatous astroglia. Using a cell type-specific experimental approach, this study aimed to determine the value of astroglial NF-κB as a potential treatment target for immunomodulation in experimental mouse glaucoma. Methods: Neuroinflammatory and neurodegenerative outcomes of experimental glaucoma were comparatively analyzed in mice with or without cre/lox-based conditional deletion of astroglial IκKβ, which is the main activating kinase involved in IκB degradation through the canonical pathway of NF-κB activation. Glial responses and the inflammatory status of the retina and optic nerve were analyzed by cell morphology and cytokine profiling, and neuron structure and function were analyzed by counting retinal ganglion cell (RGC) axons and somas and recording pattern electroretinography (PERG) responses. Results: Analysis of glial inflammatory responses showed immunomodulatory outcomes of the conditional transgenic deletion of IκKβ in astroglia. Various pro-inflammatory cytokines known to be transcriptional targets for NF-κB exhibited decreased production in IκKβ-deleted astroglia, which included TNF-α that can induce RGC apoptosis and axon degeneration during glaucomatous neurodegeneration. Indeed, transgenic modulation of inflammatory responses by astroglial IκKβ deletion reduced neurodegeneration at different neuronal compartments, including both RGC axons and somas, and protected PERG responses.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transgenic inhibition of astroglial NF-κB restrains the neuroinflammatory and neurodegenerative outcomes of experimental mouse glaucoma

Yang

Zeng

Barış

et al. 2020

J Neuroinflammation

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“…Among optic nerve diseases, glaucoma, which represents the second most common cause of blindness in the world and is expected to affect about 80 million people worldwide by 2020, is more often associated with elevated IOP that leads to RGC degeneration with consequent alterations of the visual function [1]. Since RGCs play a pivotal role in the process of vision, their degeneration, which begins as an early focal injury to the axons and progresses to apoptotic death, results in a gradual loss of visual acuity that, if left untreated, leads to irreversible blindness [38].…”

Section: Discussionmentioning

confidence: 99%

Protective Efficacy of a Dietary Supplement Based on Forskolin, Homotaurine, Spearmint Extract, and Group B Vitamins in a Mouse Model of Optic Nerve Injury

et al. 2019

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Glaucoma is a multifactorial blinding disease with a major inflammatory component ultimately leading to apoptotic retinal ganglion cell (RGC) death. Pharmacological treatments lowering intraocular pressure can help slow or prevent vision loss although the damage caused by glaucoma cannot be reversed. Recently, nutritional approaches have been evaluated for their efficacy in preventing degenerative events in the retina although mechanisms underlying their effectiveness remain to be elucidated. Here, we evaluated the efficacy of a diet supplement consisting of forskolin, homotaurine, spearmint extract, and vitamins of the B group in counteracting retinal dysfunction in a mouse model of optic nerve crush (ONC) used as an in vivo model of glaucoma. After demonstrating that ONC did not affect retinal vasculature by fluorescein angiography, we determined the effect of the diet supplement on the photopic negative response (PhNR) whose amplitude is strictly related to RGC integrity and is therefore drastically reduced in concomitance with RGC death. We found that the diet supplementation prevents the reduction of PhNR amplitude (p < 0.001) and concomitantly counteracts RGC death, as in supplemented mice, RGC number assessed immunohistochemically is significantly higher than that in non-supplemented animals (p < 0.01). Major determinants of the protective efficacy of the compound are due to a reduction of ONC-associated cytokine secretion leading to decreased levels of apoptotic markers that in supplemented mice are significantly lower than in non-supplemented animals (p < 0.001), ultimately causing RGC survival and ameliorated visual dysfunction. Overall, our data suggest that the above association of compounds plays a neuroprotective role in this mouse model of glaucoma thus offering a new perspective in inflammation-associated neurodegenerative diseases of the inner retina.

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“…Indeed, inhibiting apoptosis blocked RGC death in the DBA/2 chronic glaucoma model, but failed to protect optic nerve axons (Libby et al, 2005). In contrast, following optic nerve transection, SARM1 KO blocks degeneration of the severed distal axons, but does not protect against cell body death, which instead is mediated by retrograde axonal signals that activate apoptosis (Welsbie et al, 2013;Simon and Watkins, 2018;Syc-Mazurek and Libby, 2019). The different requirements for SARM1 following optic nerve transection and TNF-α application are instructive.…”

Section: Sarm1 Promotes Rgc and Oligodendrocyte Death In A Neuroinflamentioning

confidence: 99%

SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration

Milbrandt

DiAntonio

2020

Journal of Cell Biology

109

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Neuroinflammation and necroptosis are major contributors to neurodegenerative disease, and axon dysfunction and degeneration is often an initiating event. SARM1 is the central executioner of pathological axon degeneration. Here, we demonstrate functional and mechanistic links among these three pro-degenerative processes. In a neuroinflammatory model of glaucoma, TNF-α induces SARM1-dependent axon degeneration, oligodendrocyte loss, and subsequent retinal ganglion cell death. TNF-α also triggers SARM1-dependent axon degeneration in sensory neurons via a noncanonical necroptotic signaling mechanism. MLKL is the final executioner of canonical necroptosis; however, in axonal necroptosis, MLKL does not directly trigger degeneration. Instead, MLKL induces loss of the axon survival factors NMNAT2 and STMN2 to activate SARM1 NADase activity, which leads to calcium influx and axon degeneration. Hence, these findings define a specialized form of axonal necroptosis. The demonstration that neuroinflammatory signals and necroptosis can act locally in the axon to stimulate SARM1-dependent axon degeneration identifies a therapeutically targetable mechanism by which neuroinflammation can stimulate axon loss in neurodegenerative disease.

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Axon injury signaling and compartmentalized injury response in glaucoma

Cited by 69 publications

References 258 publications

Transgenic inhibition of astroglial NF-κB restrains the neuroinflammatory and neurodegenerative outcomes of experimental mouse glaucoma

Transgenic inhibition of astroglial NF-κB restrains the neuroinflammatory and neurodegenerative outcomes of experimental mouse glaucoma

Protective Efficacy of a Dietary Supplement Based on Forskolin, Homotaurine, Spearmint Extract, and Group B Vitamins in a Mouse Model of Optic Nerve Injury

SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration

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