Opposing Roles for Membrane Bound and Soluble Fas Ligand in Glaucoma-Associated Retinal Ganglion Cell Death

Gregory, Meredith S.; Hackett, Caroline G.; Abernathy, Emma; Lee, Karen; Saff, Rebecca R.; Hohlbaum, Andreas M.; Moody, Krishna; Hobson, Maura W.; Jones, Alexander; Kolovou, Paraskevi E.; Karray, Saoussen; Giani, Andrea; John, Simon W. M.; Chen, Dong Feng; Marshak‐Rothstein, Ann; Ksander, Bruce R.

doi:10.1371/journal.pone.0017659

Cited by 83 publications

(107 citation statements)

References 60 publications

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“…This is further supported by the prolonged neutrophil infiltration, increased infiltration into the retina, and increased retinal damage observed in BALB(gld) mice that express a nonfunctional form of FasL. Previous studies by our laboratory and others demonstrated that within the retina, FasL is primarily expressed on retinal microglia, astrocytes, the inner nuclear layer, and the retinal pigment epithelium (45)(46)(47). Therefore, we would predict that microglia within the retina ganglion cell (RGC) layer and astrocytes that line the retina are most likely to play a critical role in inducing apoptosis of infiltrating neutrophils, resulting in reduced infiltration of neutrophil into the retina and shutting down the innate-mediated inflammation.…”

Section: Discussionsupporting

confidence: 58%

Increased Resistance to Staphylococcus aureus Endophthalmitis in BALB/c Mice: Fas Ligand Is Required for Resolution of Inflammation but Not for Bacterial Clearance

et al. 2013

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FasL was recently shown be required for bacterial clearance in C57BL/6 mice that express the FasL.1 allotype. The FasL.2 allotype is expressed in BALB/c mice and exhibits increased binding affinity to and increased cytotoxic activity against Fas ؉ target cells. Therefore, we hypothesized that BALB/c mice would be more resistant to Staphylococcus aureus-induced endophthalmitis. To test this hypothesis, C57BL/6, BALB/c, and BALB(gld) mice received intravitreal injections of 2,500 CFU of S. aureus (RN6390). Clinical examinations, electroretinography (ERG), histology, and bacterial quantification were performed at 24, 48, 72, and 96 h postinjection. The myeloperoxidase (MPO) assay was used to quantitate neutrophil infiltration. At 96 h postinfection, 86% of C57BL/6 mice presented with complete destruction of the eye, compared to only 29% of BALB/c mice with complete destruction. To our surprise, in the absence of Fas ligand, BALB(gld) mice showed no difference in bacterial clearance compared to BALB/c mice. However, histology and ERG analysis revealed increased retinal damage and significant loss of retinal function. MPO analysis revealed equal numbers of neutrophils in BALB(gld) and BALB/c mice at 24 h postinfection. However, at 48 h, the neutrophil numbers remained significantly elevated in BALB(gld) mice, correlating with the increased retinal damage observed in BALB(gld) mice. We conclude that the increased resistance to S. aureus induced endophthalmitis in BALB/c mice is not dependent upon the FasL. However, in contrast to C57BL/6 mice, FasL is required for resolution of inflammation and protecting host tissue from nonspecific damage in BALB/c mice.

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Section: Discussionsupporting

confidence: 58%

Increased Resistance to Staphylococcus aureus Endophthalmitis in BALB/c Mice: Fas Ligand Is Required for Resolution of Inflammation but Not for Bacterial Clearance

et al. 2013

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“…FasL has been shown to increase in retinal microglia in a rat model of ocular hypertension (Ju et al, 2006) and FasL-positive autoreactive T cells have been implicated in the loss of RGCs following heat shock protein immunization (Wax et al, 2008). More recently, the membrane-bound form of FasL was implicated in glaucomatous RGC degeneration (Gregory et al, 2011). Collectively, these studies support a role for Fas/CD95 in RGC death.…”

Section: Discussionmentioning

confidence: 65%

ASPP1/2 Regulate p53-Dependent Death of Retinal Ganglion Cells through PUMA and Fas/CD95 ActivationIn Vivo

et al. 2013

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The transcription factor p53 mediates neuronal death in a variety of stress-related and neurodegenerative conditions. The proapoptotic activity of p53 is tightly regulated by the apoptosis-stimulating proteins of p53 (ASPP) family members: ASPP1 and ASPP2. However, whether ASPP1/2 play a role in the regulation of p53-dependent neuronal death in the CNS is currently unknown. To address this, we asked whether ASPP1/2 contribute to the death of retinal ganglion cells (RGCs) using in vivo models of acute optic nerve damage in mice and rats. Here, we show that p53 is activated in RGCs soon after injury and that axotomy-induced RGC death is attenuated in p53 heterozygote and null mice. We demonstrate that ASPP1/2 proteins are abundantly expressed by injured RGCs, and that short interfering (si)RNA-based ASPP1 or ASPP2 knockdown promotes robust RGC survival. Comparative gene expression analysis revealed that siASPPmediated downregulation of p53-upregulated-modulator-of-apoptosis (PUMA), Fas/CD95, and Noxa depends on p53 transcriptional activity. Furthermore, siRNA against PUMA or Fas/CD95 confers neuroprotection, demonstrating a functional role for these p53 targets in RGC death. Our study demonstrates a novel role for ASPP1 and ASPP2 in the death of RGCs and provides evidence that blockade of the ASPP-p53 pathway is beneficial for central neuron survival after axonal injury.

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“…Another member of the TNF family implicated in glaucoma pathogenesis is the proapoptotic protein Fas ligand, which was found to be damaging to RGCs in DBA/2J glaucoma (Gregory et al 2011). Inhibition of Fas ligand activity prevented death of RGCs after intraocular injection of TNF-a, indicating that Fas ligand mediates TNF-a cytotoxicity in RGCs (Gregory et al 2011).…”

Section: Inflammatory Signaling Pathways In Glaucomamentioning

confidence: 99%

The Complex Role of Neuroinflammation in Glaucoma

Soto

Howell

2014

Cold Spring Harbor Perspectives in Medicine

190

156

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Opposing Roles for Membrane Bound and Soluble Fas Ligand in Glaucoma-Associated Retinal Ganglion Cell Death

Cited by 83 publications

References 60 publications

Increased Resistance to Staphylococcus aureus Endophthalmitis in BALB/c Mice: Fas Ligand Is Required for Resolution of Inflammation but Not for Bacterial Clearance

Increased Resistance to Staphylococcus aureus Endophthalmitis in BALB/c Mice: Fas Ligand Is Required for Resolution of Inflammation but Not for Bacterial Clearance

ASPP1/2 Regulate p53-Dependent Death of Retinal Ganglion Cells through PUMA and Fas/CD95 ActivationIn Vivo

The Complex Role of Neuroinflammation in Glaucoma

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