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

Abstract

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.

Irreversible Photoreceptors and RPE Cells Damage by Intravenous Sodium Iodate in Mice Is Related to Macrophage Accumulation

“…It has been reported that NaIO 3 injury mimicked nonexudative AMD, including the fundus, OCT, and histological characteristics. 13,20,32,33 In addition, the results of this study showed that the retinal blood flow was decreased after the NaIO 3 -induced RPE atrophy, similar to AMD pathology (Fig. 6).…”

“…1E). The results of earlier studies have suggested that the NaIO 3 injection induced macrophage accumulation in the retina, 33,44 and the macrophages phagocytose the melanin aggregations. 45 In addition, the expressions of the mRNA transcripts of Il-1b and Il-6, inflammatory cytokines induced from macrophages 46,47 increased at 3 days after the 40 mg/kg NaIO 3 injection (Fig.…”

Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus–like inflammation

“…This model is likely to prove useful for mechanistic studies addressing the role of TLR9, TLR7, IFN-γ, FasL, type I IFNs, and other immune mediators in CLE and for assessing a variety of therapeutic strategies for the treatment of SLE. Small-molecule FasL inhibitors are under development and have been shown to be highly effective in the blockade of FasL-dependent ocular disorders (73). Related compounds may eventually be appropriate for the treatment of FasLdependent lupus-associated skin disease.…”

“…Importantly, FasL is upregulated in the skin of CLE, but not psoriasis, patients. Small-molecule FasL inhibitors are under development and have been shown to be highly effective in the blockade of FasL-dependent ocular disorders (73). Related compounds may eventually be appropriate for the treatment of FasLdependent lupus-associated skin disease.…”

An Acute Injury Model for the Phenotypic Characteristics of Geographic Atrophy

“… 2 – 7 NaIO 3 is thought to directly affect the RPE cells with secondary effects on photoreceptors and the CC. It has been shown to induce the production of reactive oxygen species contributing to damage similar to human GA. 8 – 11 The current models using systemic delivery of NaIO 3 , however, result in widespread degeneration. The degeneration is not succinct and is not surrounded by healthy retina and choroid, as seen in human GA.…”