Zhongjie Fu

BACKGROUND: Mononuclear phagocytes contribute to pathological angiogenesis in age-related macular degeneration, a leading worldwide cause of visual impairment. However, the mechanisms that orchestrate the functions of mononuclear phagocytes remain poorly understood. TREM2 (triggering receptor on myeloid cells 2) has been shown to be crucial for the activation of mononuclear phagocytes in atherosclerosis, fatty liver disease, and Alzheimer disease. The objective of this study was to investigate the role of TREM2 in pathological angiogenesis in age-related macular degeneration. METHODS: C57BL/6J and Trem2 knockout mice were subjected to laser-induced choroidal neovascularization, a model of choroidal neovascular age-related macular degeneration. Purified bovine sulfatide and agonist anti-TREM2 antibody was used to activate TREM2 signaling. The expression of TREM2 or downstream signals were assessed with immunohistochemistry or real-time quantitative PCR. In vitro murine macrophage RAW264.7 cells were used to investigate the direct impact of sulfatide on inflammatory and phagocytic responses. RESULTS: We found that pharmacological activation of TREM2 suppressed laser-induced choroidal neovessel formation. The activation of TREM2 in mononuclear phagocytes suppressed TNF (tumor necrosis factor) and subsequently promoted phagocytosis. CONCLUSIONS: These findings demonstrate that activation of TREM2 in mononuclear phagocytes suppresses the proinflammatory response, promotes phagocytosis, and impedes choroidal neovessel formation. Our study provides insight into the critical role of TREM2 in pathological angiogenesis.

Rationale: Pathological retinal angiogenesis with irregular and fragile vessels (also termed neovascularization, a response to hypoxia and dysmetabolism) is a leading cause of vision loss in all age groups. This process is driven in part through the energy deficiency in retinal neurons. Sustaining neural retinal metabolism with adequate nutrient supply may help prevent vision-threatening neovascularization. Low circulating serine levels are associated with neovascularization in macular telangiectasia and altered serine/glycine metabolism has been suggested in retinopathy of prematurity. We here explored the role of serine metabolism in suppressing hypoxia-driven retinal neovascularization using oxygen-induced retinopathy (OIR) mouse model.

Background: Retinopathy of prematurity (ROP) is the major cause of blindness in children. It is a biphasic disease with retinal vessel growth cessation and loss (Phase I) followed by uncontrolled retinal vessel growth (Phase II). Folate is an essential nutrient for fetal development and growth. Premature infants have a high risk for folate deficiency. However, the contribution of folate to ROP risk remains unknown. Methods: In mouse oxygen-induced retinopathy (OIR), the nursing dams were fed with a folic acid-deficient or control diet after delivery until the end of hyperoxia. Alternatively, pups received direct injection of either folic acid or vehicle during Phase I hyperoxia. Genes involved in the folate cycle and angiogenic responses were examined using real-time PCR. Total retinal folate levels were measured with the Lactobacillus casei assay. Results: Maternal folic acid deficiency in early life exacerbated pathological retinal vessel growth, while supplementation with folic acid suppressed it. Genes involved in the folate cycle were downregulated in Phase I OIR retinas and were highly expressed in Müller glia. Folic acid reduced pro-angiogenic signaling in cultured rat retinal Müller glia in vitro. Conclusions: Appropriate supplementation of folic acid might be a new and safe treatment for ROP at an early stage.

Objective: Pathological retinal neovascularization is vision-threatening. In mouse oxygen-induced retinopathy (OIR) we sought to define mitochondrial respiration changes longitudinally during hyperoxia-induced vessel loss and hypoxia-induced neovascularization, and to test interventions addressing those changes to prevent neovascularization. Methods: OIR was induced in C57BL/6J mice and retinal vasculature was examined at maximum neovessel formation. We assessed total proteome changes and the ratio of mitochondrial to nuclear DNA copy numbers (mtDNA/nDNA) of OIR vs. control retinas, and mitochondrial oxygen consumption rates (OCR) in ex vivo OIR vs. control retinas (BaroFuse). Pyruvate vs. vehicle control was supplemented to OIR mice either prior to or during neovessel formation. Results: In OIR vs. control retinas, global proteomics showed decreased retinal mitochondrial respiration at peak neovascularization. OCR and mtDNA/nDNA were also decreased at peak neovascularization suggesting impaired mitochondrial respiration. In vivo pyruvate administration during but not prior to neovessel formation (in line with mitochondrial activity time course) suppressed NV. Conclusions: Mitochondrial energetics were suppressed during retinal NV in OIR. Appropriately timed supplementation of pyruvate may be a novel approach in neovascular retinal diseases.

Appropriate nutrients are essential for cellular function. Dietary components can alter the risk of systemic metabolic diseases, including cardiovascular diseases, cancer, diabetes, and obesity, and can also affect retinal diseases, including age-related macular degeneration, diabetic retinopathy, and glaucoma. Dietary nutrients have been assessed for the prevention or treatment of retinal ischemic diseases and the diseases of aging. In this article, we review clinical and experimental evidence concerning the potential of some nutritional supplements to prevent or treat retinal ischemic diseases and provide further insights into the therapeutic effects of nutritional supplementation on retinopathies. We will review the roles of nutrients in preventing or protecting against retinal ischemic diseases.

Purpose: To qualitatively and quantitatively characterise the genotypes and phenotypes of Bietti’s crystalline dystrophy (BCD) in a cohort of patients.Design: Cross-sectional and observational study.Methods: Clinically confirmed BCD patients were recruited for genotyping and phenotyping. Multiple retinal imaging modalities were employed. Atrophy in the fovea was adopted as major consideration for staging strategy, while percentage area of autofluorescence (AF) atrophy (PAFA) in the macula was determined for quantitation.Results: In 74 clinically diagnosed BCD patients, c.802–8_810del17insGC was shown the predominant variant of theCYP4V2gene (allele frequency 55.4%). Sixty-two cases (123 eyes) with full imaging data were classified according to a modified criterion into stages 1 (n=8, 6.50%), 2A (n=9, 7.32%), 2B (n=17, 13.82%), 3A (n=30, 24.39%) and 3B (n=59, 47.97%). The eyes of the stage 2B were particularly deemed ‘high risk’ due to atrophy near fovea, while in stage 3A, though with remarkable foveal atrophy, preserved retinal pigment epithelium/photoreceptor islands near the fovea were found in 14 eyes. A tendency of increase in PAFA with age was found (r_s=0.31, p=0.014). Significant PAFA increase was shown through stages 1 to 3B, and best-corrected visual acuity (BCVA, Logarithm of the Minimum Angle of Resolution) was shown to moderately correlate with PAFA (r_s=0.56, p<0.001).Conclusion: The PAFA might be an efficient biomarker for BCD severities correlating with BCVA. The highly heterogeneous chorioretinopathy and BCVA of BCD cases appear to be associated with disease stages, progression types and patients’ ages. Foveal involvement should be of a major concern for consideration of potential therapeutic intervention.