Light-dependent induction of Edn2 expression and attenuation of retinal pathology by endothelin receptor antagonists in Prominin-1- deficient mice

Retinitis pigmentosa (RP) and macular dystrophy (MD) are prevalent retinal degenerative diseases associated with gradual photoreceptor death. These diseases are often caused by genetic mutations that result in degeneration of the retina postnatally after it has fully developed. The Prominin-1 gene (Prom1) is a causative gene for RP and MD, and Prom1- knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and stenosis of retinal blood vessels. The mechanisms underlying progression of such degeneration have remained unknown, however. We here analysed early events associated with retinal degeneration in Prom1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. High-throughput analysis revealed that expression of the endothelin-2 gene (Edn2) was markedly up-regulated in the Prom1-deficient retina during this period. Expression of Edn2 was also induced by light stimulation in Prom1-KO mice that had been reared in the dark. Finally, treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis, and retinal vessel stenosis in Prom1-KO mice. Our findings suggest that inhibitors of endothelin signalling may delay the progression of RP and MD and therefore warrant further study as potential therapeutic agents for these diseases

Inhibitory effect of nintedanib on VEGF secretion in retinal pigment epithelial cells induced by exposure to a necrotic cell lysate.

Necrosis is a form of cell death that results in rupture of the plasma membrane and the release of cellular contents, and it can give rise to sterile inflammation in the retina and other tissues. The secretion of vascular endothelial growth factor (VEGF) by retinal pigment epithelial (RPE) cells contributes to retinal homeostasis as well as to pathological angiogenesis. We have now examined the effect of a necrotic cell lysate prepared from human RPE cells (NLR) on the release of VEGF by healthy RPE cells. We found that NLR markedly increased the release of VEGF from RPE cells and that this effect was attenuated by nintedanib, a multiple receptor tyrosine kinase inhibitor, whereas it was unaffected by inhibitors of NF-κB signaling or of caspase-1. NLR also induced the phosphorylation of extracellular signal-regulated kinase (Erk) and signal transducer and activator of transcription 3 (Stat3) in a manner sensitive to inhibition by nintedanib, although inhibitors of Erk and Stat3 signaling pathways did not affect NLR-induced VEGF secretion. In addition, nintedanib attenuated the development of choroidal neovascularization in mice. Our results have thus shown that a necrotic lysate of RPE cells induced VEGF secretion from healthy RPE cells and that this effect was mediated by receptor tyrosine kinase signaling. They therefore suggest that VEGF secretion by healthy RPE cells is a potential therapeutic target for retinal diseases associated with sterile inflammation and pathological angiogenesis

Poor prognosis of elderly individuals >80 years of age with acute retinal necrosis

Purpose: To report the clinical features and prognosis of acute retinal necrosis (ARN) in elderly (>80 years of age) individuals. Methods: Six consecutive patients with unilateral ARN who attended the Department of Ophthalmology at Yamaguchi University Hospital between 2014 and 2015 were retrospectively reviewed. Clinical characteristics, causative virus, time from symptom onset to physician visit, visual acuity at presentation and final visit, and treatment were evaluated and compared between the three elderly and three middle-aged (<80 years) patients. Results: Varicella zoster virus (VZV) DNA was detected in aqueous humor by the polymerase chain reaction in all six cases. The mean ± SD time between symptom onset and medical attention was 18.0 ± 8.7 and 8.3 ± 1.5 days in the elderly and middle-aged groups, respectively. All patients were treated with intravenous aciclovir, oral prednisolone, and a nonsteroidal anti-inflammatory drug, and five of the six patients also received oral valaciclovir and underwent vitrectomy. The final best corrected visual acuity of the affected eye was worse for the elderly patients (20/400, hand motion, and light perception negative) than for the middle-aged patients (20/15, 20/50, and 20/25). Conclusions and importance: ARN in the elderly individuals of the present study was caused by VZV infection and associated with a poorer visual prognosis compared with that of middle-aged patients. A delay in the onset of antiviral treatment might contribute to the poor prognosis of elderly patients with ARN

Dendritic cells mediate the anti-inflammatory action of omega-3 long-chain polyunsaturated fatty acids in experimental autoimmune uveitis.

We previously showed that dietary omega (ω)-3 long-chain polyunsaturated fatty acids (LCPUFAs) suppress inflammation in mice with experimental autoimmune uveitis (EAU). We have now investigated the role of antigen presenting cells (APCs) in this action of ω-3 LCPUFAs. C57BL/6 mice were fed a diet supplemented with ω-3 or ω-6 LCPUFAs for 2 weeks, after which splenocytes were isolated from the mice and cocultured with CD4+ T cells isolated from mice with EAU induced by injection of a human interphotoreceptor retinoid-binding protein peptide together with complete Freund's adjuvant. The proliferation of and production of interferon-γ and interleukin-17 by T cells from EAU mice in vitro were attenuated in the presence of splenocytes from ω-3 LCPUFA-fed mice as compared with those from mice fed ω-6 LCPUFAs. Splenocyte fractionation by magnetic-activated cell sorting revealed that, among APCs, dendritic cells (DCs) were the target of ω-3 LCPUFAs. Adoptive transfer of DCs from mice fed ω-3 LCPUFAs attenuated disease progression in EAU mice as well as the production of pro-inflammatory cytokines by T cells isolated from these latter animals. The proliferation of T cells from control Balb/c mice was also attenuated in the presence of DCs from ω-3 LCPUFA-fed mice as compared with those from ω-6 LCPUFA-fed mice. Furthermore, T cell proliferation in such a mixed lymphocyte reaction was inhibited by prior exposure of DCs from mice fed an ω-6 LCPUFA diet to ω-3 LCPUFAs in vitro. Our results thus suggest that DCs mediate the anti-inflammatory action of dietary ω-3 LCPUFAs in EAU

Early manifestations and differential gene expression associated with photoreceptor degeneration in Prom1-deficient retina

Retinitis pigmentosa (RP) and macular dystrophy (MD) are characterized by gradual photoreceptor death in the retina and are often associated with genetic mutations, including those in the prominin-1 (Prom1) gene. Prom1-knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and constriction of retinal blood vessels. The mechanisms underlying such degeneration have remained unclear, however. We here analysed early events associated with retinal degeneration in Prom1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. Whereas gene expression was not affected at 2 weeks, the expression of several genes was altered at 3 weeks in the Prom1-KO retina, with the expression of that for endothelin-2 (Edn2) being markedly upregulated. Expression of Edn2 was also induced by light stimulation in Prom1-KO mice reared in the dark. Treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis and retinal vessel stenosis in Prom1-KO mice. Our findings thus reveal early manifestations of retinal degeneration in a model of RP/MD and suggest potential therapeutic agents for these diseases. This article has an associated First Person interview with the first author of the paper

Influence of extended depth of focus intraocular lenses on visual field sensitivity.

PurposeTo investigate the influence of EDOF IOLs, TECNIS Symfony® (Johnson & Johnson Surgical Vision, Inc.), on visual field sensitivity and to compare the IOLs with other kinds of IOLs.MethodsThe subjects included the normal fellow eyes of patients who underwent the Humphrey Field Analyzer (HFA) 30-2 with Swedish Interactive Threshold Algorithm Fast within 6 months after cataract due to glaucoma or suspected glaucoma. Each parameter of HFA was compared among eyes implanted with TENIS Symfony® (EDOF group), diffractive bifocal IOLs (bifocal group), and monofocal IOLs (monofocal group).ResultsThe total of 76 eyes, including 24 eyes in the EDOF group, 26 eyes in the bifocal group, and 26 eyes in the monofocal group, were included in this study. Mean deviation (MD) of HFA was -0.24±0.58 dB in the EDOF group, -1.38±0.58 dB in the bifocal group, and 0.02±0.44 dB in the monofocal group. Foveal threshold (FT) of HFA was 35.8±1.6 dB in the EDOF group, 33.6±1.7 dB in the bifocal group, and 36.6±1.4 dB in the monofocal group. In both MD and FT, there was significant difference between the bifocal group and the others (pConclusionTECNIS Symfony® may have little influence on visual field sensitivity, whereas diffractive bifocal IOLs decrease visual field sensitivity