The retina is a highly organized part of the central nervous system that converts incoming light into electrical signals, which are transmitted to the brain to produce complex visual perceptions. It consists of a diverse network of neuron types, glial cells, and vascular cells, making it one of the most metabolically active tissues. As a result, the retina is supplied with blood by two well-coordinated vascular systems, the retinal and choroidal systems, which maintain an optimal microenvironment for neurons and glial cells. In addition to cells responsible for visual function, the retina also contains intrinsically photosensitive retinal ganglion cells (ipRGCs), which regulate the development of the visual system and non-image-forming functions of the eye, such as circadian rhythm synchronization and the pupillary light reflex [1, 2]. These cells project to brain regions such as the hypothalamic suprachiasmatic nucleus and the olivary pretectal nucleus. Recent studies suggest that ipRGCs may also influence peripheral metabolic processes, such as glucose homeostasis, through both clock-dependent and independent mechanisms, indicating that abnormal light exposure could contribute to the development of cardiometabolic diseases [3]. Environmental factors, such as traffic noise and particulate matter, have also been shown to trigger cardiometabolic diseases that affect the retina [4]. Oxidative stress and tissue inflammation, driven by infiltrating immune cells, are significant contributors to these pathological events [5]. Therefore, beyond efforts to reduce environmental pollution and protect society from harmful pollutants, it is essential to understand the complex redox, immune, and cell-to-cell interaction mechanisms within the retina. This knowledge is crucial for preventing and treating diseases such as age-related macular degeneration and diabetic retinopathy [6].

Given the complex and multifaceted nature of retinal diseases, understanding the underlying immune mechanisms, vascular factors, and molecular pathways is crucial for advancing therapeutic strategies. This Special Issue features review and original research articles on various aspects of retinal immune mechanisms, the blood-retinal barrier, vascular endothelial growth factor (VEGF), and the specific functions of nitric oxide synthases in health and disease.

Zhu et al. [7] summarized the existing literature on the mechanisms establishing the immune privilege in the retina, including the inner and outer blood-retinal barriers, microglia, cell membrane-bound proteins, and the suppression of systemic immune responses. The publication highlights the critical roles of microglia and the retinal pigment epithelium in maintaining the structural integrity of the retina. Microglia modulate retinal immune responses and interact with retinal blood vessels by secreting trophic and angiogenic factors, while retinal pigment epithelium cells limit the entry of toxic blood and immune components into the neuroretina and secrete various immunosuppressive factors. The study also explores potential therapeutic strategies aimed at modulating microglia activity and retinal pigment epithelium function.

Immunological factors are also central to the study by Tang et al. [8], who investigated cytokine expression in the aqueous humor of primary angle-closure glaucoma patients and in explanted rat retinas exposed to elevated ambient pressure. There is growing evidence that immune responses within the nervous system contribute to glaucoma onset and progression, with elevated intraocular pressure potentially triggering proinflammatory cytokine secretion. Tang and colleagues [8] reported significant differences in the inflammatory cytokine profiles between glaucoma patients, pressure-exposed retinas, and their respective controls. Notably, cytokine profile alterations varied considerably between the aqueous humor of glaucoma patients and the retinas of rats exposed to high pressure, suggesting that the immunological processes triggered by elevated intraocular pressure are complex and warrant further investigation as potential therapeutic targets.

Wichrowska et al. [9] conducted a review of studies assessing the impact of anti-VEGF treatment on the retinal nerve fiber layer in patients with wet age-related macular degeneration. The nerve fiber layer, the innermost retinal layer exposed to intravitreal drugs, was the focus of the review. Most research supports the safety of anti-VEGF treatment regarding the retinal nerve fiber layer, although some studies noted potential effects in long-term observations after multiple injections. The article also addresses possible biases affecting study outcomes, such as small sample sizes, variations among anti-VEGF drugs, differences in age groups, follow-up durations, and the use of appropriate control groups.

In another review article, our group provided a comprehensive overview on the roles of individual nitric oxide synthase (NOS) isoforms in both normal retinal vascular physiology and in pathological conditions [10]. Under physiological conditions, endothelial NOS maintains retinal perfusion, but it can become dysfunctional under pathological conditions, amplifying generation of reactive oxygen species and contributing to endothelial dysfunction and cellular harm. Additionally, excessive nitric oxide production by inducible NOS triggers nitro-oxidative stress, further exacerbating vascular endothelial dysfunction and retinal cell injury. Strategies to restore correct NOS function involve modulating arginase expression or activity, supplementing with the co-factor tetrahydrobiopterin, and selectively targeting specific NOS isoforms to mitigate nitro-oxidative stress.

Finally, Son et al. [11] examined the distribution and morphology of starburst amacrine cells in the retinas of diabetic mice. These interneurons, which secrete both excitatory acetylcholine and inhibitory gamma-aminobutyric acid, play crucial roles in retinal development and visual motion perception. The authors observed a decline in the density of these cells in both the ganglion cell layer and the inner nuclear layer as diabetes progressed. Additionally, they identified cell body deformation, abnormal cell aggregation, and dendritic branch loss in diabetic retinas. Possible mechanisms for these changes include hyperglycemia-induced activation of cell death pathways, inflammation, depletion of supporting glial cells, and loss of synaptic connections with other neurons, such as dopaminergic amacrine cells. The findings suggest that starburst amacrine cells may play a key role in the pathophysiology of diabetic retinopathy and could serve as diagnostic tools and therapeutic targets.

Within the retina, starburst amacrine cells are the sole source of acetylcholine, which activates nicotinic and muscarinic receptors in retinal ganglion cells, thereby enhancing their viability [12, 13]. Consequently, the loss of starburst amacrine cells may impair retinal ganglion cell viability through acetylcholine deprivation. Similar findings have been observed in Parkinson’s disease patients, where a reduction in starburst amacrine cells is thought to result from the loss of synaptic input from dopaminergic amacrine cells [14]. Indeed, retinal ganglion cells, including ipRGCs, appear to be reduced in Parkinson’s disease, leading to visual function impairments and circadian rhythm disturbances [15]. These observations suggest that dopamine is crucial for the survival of both cholinergic amacrine cells and retinal ganglion cells. However, the role of starburst amacrine cells and their neurotransmitters in the survival of other retinal neurons, as well as their susceptibility to hyperglycemia, oxidative stress, and inflammation, remains to be clarified in the context of common retinal diseases, including diabetic retinopathy and glaucoma. Furthermore, the impact of individual retinal diseases on the function and viability of specific retinal cell types, as well as their influence on visual function, circadian rhythm, and cardiometabolic health, remains a crucial area of research. In summary, this Special Issue presents significant findings on retinal physiology and pathophysiology, offering novel approaches for diagnosing and treating retinal diseases while also highlighting areas for further research.

Acknowledgment

Not applicable.