Membrane-bound and soluble Fas ligands have opposite functions in photoreceptor cell death following separation from the retinal pigment epithelium

Matsumoto, Hidetaka; Murakami, Yusuke; Kataoka, Keiko; Notomi, Shoji; Mantopoulos, Dimosthenis; Trichonas, George; Miller, Joan W.; Gregory, Meredith S.; Ksander, Bruce R.; Marshak‐Rothstein, Ann; Vavvas, Demetrios G.

doi:10.1038/cddis.2015.334

Cited by 34 publications

(39 citation statements)

References 50 publications

(82 reference statements)

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“…We also assessed for the activation of microglia and or infiltration of macrophages, which is often associated with outer retinal injury and activation of Fas-mediated cell death. 8,24,25 We observed that exposure to NaIO3 resulted in more Iba1-positive cells in retina flat mounts, and that this was significantly reduced by Met12- as compared to mMet12-treated eyes (Fig. 4B).…”

Section: Resultsmentioning

confidence: 82%

Protective Effect of Met12, a Small Peptide Inhibitor of Fas, on the Retinal Pigment Epithelium and Photoreceptor After Sodium Iodate Injury

Xiao

Yao

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeA major problem in macular degeneration is the inability to reduce RPE and photoreceptor death. These cells die by necroptosis and apoptosis, respectively, but the upstream activator(s) of these death pathways is unknown. In this study, we use the sodium iodate (NaIO3) model of oxidative stress to test the hypothesis that activation of the Fas receptor contributes to the death of the RPE and photoreceptors.MethodsSodium iodate was injected in Brown-Norway rats via femoral vein injection. Both in vivo (fundus photography, optical coherence tomography, and fluorescein angiography) and ex vivo (histology, immunohistochemistry, Western blot, and RT-PCR) analyses of the RPE and retina were conducted at baseline, as well as at various times post NaIO3 injection. The ability of intravitreal injection of Met12, a small peptide inhibitor of the Fas receptor, to prevent RPE and photoreceptor cell death was assessed.ResultsInjection of NaIO3 led to Fas-mediated activation of both necroptosis and apoptosis in the RPE and photoreceptors, respectively. This was accompanied by a significant increase in the number of microglia/macrophages in the outer retina. Met12 significantly reduced the activation of the Fas-mediated death pathways, resulting in reduced RPE and photoreceptor death and a decreased immune response.ConclusionsOur results demonstrate that NaIO3 activates Fas-mediated cell death, both in the RPE and photoreceptor, and that a small peptide antagonist of the Fas receptor, Met12, significantly reduces the extent of this cell death. These findings suggest a role for Fas inhibition to protect the RPE and photoreceptors from death due to oxidative stress.

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Section: Resultsmentioning

confidence: 82%

Protective Effect of Met12, a Small Peptide Inhibitor of Fas, on the Retinal Pigment Epithelium and Photoreceptor After Sodium Iodate Injury

Xiao

Yao

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…Exactly how the balance between sFasL and mFasL shifts during diseases such as glaucoma is unclear, but our data demonstrate that mFasL is definitely the pathogenic isoform. We have explored the role of mFasL vs sFasL in gene-targeted ΔCS mice where the FasL cleavage site has been mutated and can no longer be cleaved by metalloproteinases (27, 67). In ΔCS mice, total FasL expression is controlled by the endogenous FasL promoter as in WT mice, but in ΔCS mice, cells that normally express FasL can only make mFasL and not sFasL.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Soluble Fas Ligand following Adeno-Associated Virus Gene Therapy Prevents Retinal Ganglion Cell Death in Chronic and Acute Murine Models of Glaucoma

Krishnan

Fei

Jones

et al. 2016

The Journal of Immunology

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Glaucoma is a multifactorial disease resulting in the death of retinal ganglion cells (RGCs) and irreversible blindness. Glaucoma-associated RGC cell death depends on the pro-apoptotic and proinflammatory activity of membrane-bound FasL (mFasL). In contrast to mFasL, the natural soluble FasL cleavage product (sFasL) inhibits mFasL-mediated apoptosis and inflammation and is therefore a mFasL antagonist. DBA/2J (D2) mice spontaneously develop glaucoma and predictably RGC destruction is exacerbated by expression of a mutated membrane-only FasL (mFasL) gene that lacks the extracellular cleavage site. Remarkably, one time intraocular adeno-associated virus-mediated gene delivery of sFasL (AAV2.sFasL) provides complete and sustained neuroprotection in both the chronic D2 and acute microbead-induced models of glaucoma, even in the presence of elevated intraocular pressure (IOP). This protection correlated with inhibition of glial activation, reduced production of TNFα, and decreased apoptosis of RGCs and loss of axons. These data indicate that cleavage of FasL under homeostatic conditions, and the ensuing release of sFasL, normally limits the neurodestructive activity of FasL. The data further support the notion that sFasL, and not mFasL, contributes to the immune privileged status of the eye.

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“…Indeed, using the retinal detachment model, we found upregulation of expression and phosphorylation of RIPK along with activation of caspases ( Figure 3 ). 160 , 167 , 172 , 173 When we tried to inhibit RIPK or caspases in isolation, no major effect on photoreceptor loss was observed. 167 In contrast, combined treatment led to significant rescue.…”

Section: Future Treatments—neuroprotectionmentioning

confidence: 99%

Advances in Age-related Macular Degeneration Understanding and Therapy

Miller¹,

Bagheri²,

Vavvas³

2017

US Ophthalmic Review

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While the development of anti-vascular endothelial growth factor (anti-VEGF) as a therapy for neovascular age-related macular degeneration (AMD) was a great success, the pathologic processes underlying dry AMD that eventually leads to photoreceptor dysfunction, death, and vision loss remain elusive to date, with a lack of effective therapies and increasing prevalence of the disease. There is an overwhelming need to improve the classification system of AMD, to increase our understanding of cell death mechanisms involved in both neovascular and non-neovascular AMD, and to develop better biomarkers and clinical endpoints to eventually be able to identify better therapeutic targets—especially early in the disease process. There is no doubt that it is a matter of time before progress will be made and better therapies will be developed for non-neovascular AMD.

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Membrane-bound and soluble Fas ligands have opposite functions in photoreceptor cell death following separation from the retinal pigment epithelium

Cited by 34 publications

References 50 publications

Protective Effect of Met12, a Small Peptide Inhibitor of Fas, on the Retinal Pigment Epithelium and Photoreceptor After Sodium Iodate Injury

Protective Effect of Met12, a Small Peptide Inhibitor of Fas, on the Retinal Pigment Epithelium and Photoreceptor After Sodium Iodate Injury

Overexpression of Soluble Fas Ligand following Adeno-Associated Virus Gene Therapy Prevents Retinal Ganglion Cell Death in Chronic and Acute Murine Models of Glaucoma

Advances in Age-related Macular Degeneration Understanding and Therapy

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