Non-exudative age-related macular degeneration (AMD) involves retinal pigment epithelium (RPE) dysfunction and has been linked to altered intraocular immunity. Our investigation focuses on immune cell subsets and inflammation-associated factors in the eyes with early and intermediate AMD. We observed elevated levels of activated natural killer (NK) cells and interferon-γ, concurrent with reduced myeloid-derived suppressor cells (MDSCs) and adenosine in AMD eyes. Aqueous humor from AMD patients had diminished ability to dampen NK cell activation, an effect rescued by adenosine supplementation. The Cryba1 cKO mouse model recapitulated these immune alterations, and single-cell RNA-sequencing identified NK cell-related genes and NK cell-RPE interactions. Co-culture of activated NK cells with RPE cells induced barrier dysfunction and Gasdermin-E driven pyroptosis providing a functional link relevant to AMD. These findings suggest a double-hit model where elevated immune activation and loss of immune dampening mechanisms drive AMD progression. Resetting the intraocular immune balance may be a promising therapeutic strategy for managing early and intermediate AMD.
Introduction Macular pigment (MP), consisting of lutein (L) and zeaxanthin (Z), is believed to provide retinal protection against photo-oxidative damage. The objective of the study was to evaluate the effect of lutein and zeaxanthin complex 5:1 (extracted from marigold flowers) supplementation on macular pigment optical density (MPOD), contrast sensitivity, and quality of sleep in healthy subjects who exposed themselves to an electronic gadget screen for a minimum of 8 hours every day. This study also aimed to assess the long-term safety of the supplement by administering it for 8 months in one of the groups. The study also assessed the retention effects of lutein and zeaxanthin on MPOD after discontinuation of supplementation. Methods The study was registered with the Clinical Trial Registry of India (CTRI/2022/12/048392). Subjects were screened as per the defined inclusion and exclusion criteria. Subjects aged 18-55 years with a screen time of at least 8 hours daily and MPOD values below 0.8 were recruited. The study, conducted at Narayana Nethralaya Super Specialty Eye Hospital, Bangalore, spanned from December 2022 to May 2024. This was a randomized, placebo-controlled, crossover study. Of the 96 volunteers screened for this study, 71 were recruited, and 60 completed the study. Subjects were divided into 3 groups, viz. A, B, and C. Group A received lutein 10mg and zeaxanthin 2mg twice daily for the first four months, had a wash-off period of 15 days, and continued with the same supplementation for the remaining four months. Group B received lutein 10mg and zeaxanthin 2mg twice daily for the first four months, had a wash-off period of 15 days, and then switched over to a placebo for the next four months. Group C received a Placebo for the first 4 months, had a wash-off period of 15 days, and then switched over to lutein 10mg and zeaxanthin 2mg for the next four months. All the subjects were given either, lutein and zeaxanthin complex-5:1 or placebo capsules as per the randomization chart prepared computationally. Subjects were analyzed for their MPOD values, contrast sensitivity scores, and quality of sleep. Intraocular pressure, retinal thickness, renal function tests, and liver function tests were conducted during visits to ensure clinical safety. Results After supplementation with the lutein-zeaxanthin complex-5:1, the average MPOD (at 1ᴏ eccentricity) increased significantly. At the first visit, the mean MPOD for Groups A, B, and C were 0.3, 0.22, and 0.29 (right eye) and 0.31, 0.27, and 0.27 (left eye), respectively. At the second visit, these values were 0.61, 0.66, and 0.21 (right eye) and 0.54, 0.53, and 0.2 (left eye). By the third visit, the mean MPOD values were 0.7, 0.65, and 0.38 (right eye) and 0.66, 0.53, and 0.36 (left eye). Supplementation significantly improved MPOD, contrast sensitivity, and the quality of sleep compared to placebo. Conclusions The supplementation with lutein and zeaxanthin resulted in higher MPOD values as compared to that of the placebo. This intervention also led to improvement in contrast sensitivity and quality of sleep. Lutein and zeaxanthin complex-5:1 may be a promising remedial measure for increasing the MPOD of people exposed to prolonged screen time.
Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults and remains an important public health issue worldwide. Here we demonstrate that the expression of stimulator of interferon genes (STING) is increased in patients with DR and animal models of diabetic eye disease. STING has been previously shown to regulate cell senescence and inflammation, key contributors to the development and progression of DR. To investigate the mechanism whereby STING contributes to the pathogenesis of DR, diabetes was induced in STING-KO mice and STINGGT (loss-of-function mutation) mice, and molecular alterations and pathological changes in the retina were characterized. We report that retinal endothelial cell senescence, inflammation, and capillary degeneration were all inhibited in STING-KO diabetic mice; these observations were independently corroborated in STINGGT mice. These protective effects resulted from the reduction in TBK1, IRF3, and NF-κB phosphorylation in the absence of STING. Collectively, our results suggest that targeting STING may be an effective therapy for the early prevention and treatment of DR.
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