Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration

S100B is a Ca2+ -binding protein mainly concentrated in astrocytes. Its levels in biological fluids (cerebrospinal fluid, peripheral and cord blood, urine, saliva, amniotic fluid) are recognized as a reliable biomarker of active neural distress. Although the wide spectrum of diseases in which the protein is involved (acute brain injury, neurodegenerative diseases, congenital/perinatal disorders, psychiatric disorders) reduces its specificity, its levels remain an important aid in monitoring the trend of the disorder. Mounting evidence now points to S100B as a Damage-Associated Molecular Pattern molecule which, when released at high concentration, through its Receptor for Advanced Glycation Endproducts, triggers tissue reaction to damage in a series of different neural disorders. This review addresses this novel scenario, presenting data indicating that S100B levels and/or distribution in the nervous tissue of patients and/or experimental models of different neural disorders, for which the protein is used as a biomarker, are directly related to the progress of the disease: acute brain injury (ischemic/hemorrhagic stroke, traumatic injury), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis), congenital/perinatal disorders (Down syndrome, spinocerebellar ataxia-1), psychiatric disorders (schizophrenia, mood disorders), inflammatory bowel disease. In many cases, over-expression/administration of the protein induces worsening of the disease, whereas its deletion/inactivation produces amelioration. This review points out that the pivotal role of the protein resulting from these data, opens the perspective that S100B may be regarded as a therapeutic target for these different diseases, which appear to share some common features reasonably attributable to neuroinflammation, regardless their origin.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.14574

The S100B story: from biomarker to active factor in neural injury.

Inflammation in Glaucoma: From the back to the front of the eye, and beyond.

Microglia, the primary resident immune cell type, constitute a key population of glia in the retina. Recent evidence indicates that microglia play significant functional roles in the retina at different life stages. During development, retinal microglia regulate neuronal survival by exerting trophic influences and influencing programmed cell death. During adulthood, ramified microglia in the plexiform layers interact closely with synapses to maintain synaptic structure and function that underlie the retina's electrophysiological response to light. Under pathological conditions, retinal microglia participate in potentiating neurodegeneration in diseases such as glaucoma, retinitis pigmentosa, and age-related neurodegeneration by producing proinflammatory neurotoxic cytokines and removing living neurons via phagocytosis. Modulation of pathogenic microglial activation states and effector mechanisms has been linked to neuroprotection in animal models of retinal diseases. These findings have led to the design of early proof-of-concept clinical trials with microglial modulation as a therapeutic strategy.

Microglia in the Retina: Roles in Development, Maturity, and Disease

Incomplete response to Anti-VEGF therapy in neovascular AMD: Exploring disease mechanisms and therapeutic opportunities.

https://pureadmin.qub.ac.uk/ws/files/159952005/Retinal_Immune_Regulation_Aging_EU_PMC.pdf

Immune regulation in the aging retina.

S100B is a Ca2+ binding protein and is typically associated with brain and CNS disorders. However, the role of S100B in an inflammatory situation is not clear. The aim of the study was to determine whether S100B is likely to influence inflammation through its effect on macrophages. A murine macrophage cell line (RAW 264.7) and primary bone marrow derived macrophages were used for in vitro studies and a model of retinal inflammatory disease in which pathogenesis is highly dependent on macrophage infiltration, Experimental Autoimmune Uveoretinitis, for in vitro study. Experimental Autoimmune Uveoretinitis is a model for the human disease posterior endogenous uveoretinitis, a potentially blinding condition, with an autoimmune aetiology, that mainly affects the working age group. To date the involvement of S100B in autoimmune uveoretinitis has not been investigated. Real-time PCR array analysis on RAW 246.7 cells indicated up-regulation of gene expression for various cytokines/chemokines in response to S100B, IL-1β and CCL22 in particular and this was confirmed by real-time PCR. In addition flow cytometry and ELISA confirmed up-regulation of protein production in response to S100B for pro-IL-1β and CCL22 respectively. This was the case for both RAW 264.7 cells and bone marrow derived macrophages. Induction of EAU with retinal antigen in mice in which S100B had been deleted resulted in a significantly reduced level of disease compared to wild-type mice, as determined by topical endoscopic fundus imaging and histology grading. Macrophage infiltration was also significantly reduced in S100B deleted mice. Real-time PCR analysis indicated that this was associated with reduction in CCL22 and IL-1β in retinas from S100B knock-out mice. In conclusion S100B augments the inflammatory response in uveoretinitis and this is likely to be, at least in part, via a direct effect on macrophages.

/pdf/s100b-up-regulates-macrophage-production-of-il1b-and-ccl22-2mt1o16rfz.pdf

S100B Up-Regulates Macrophage Production of IL1β and CCL22 and Influences Severity of Retinal Inflammation

Purpose: Age-related macular degeneration (AMD) is one of the leading causes of blindness in the elderly population aged ≥60 years. Previous studies have shown that retinal pigment epithelial cell (RPE) degeneration is one of the early and crucial stages in AMD. It has been suggested that microglia and macrophages may be involved in the impairment of RPE, but how they and RPE are influenced by other factors present as AMD develops is unclear. Therefore the purpose of this study was to determine the role of macrophages in RPE degeneration in the presence of cytokines and oxidative stress likely to be present as AMD develops.Methods: A co-culture model system was set up using bone marrow-derived macrophages and brain or retinal microglia cultured with RPE. Cytokines (IL-1β, TNF-α, IFN-γ, and IL-6) and oxidized low-density lipoprotein were included in the culture at concentrations estimated to be likely during AMD, and apoptosis of RPE cells determined using flow cytometry to detect annexin V.Results...

Retinal Pigment Epithelial Cell Apoptosis is Influenced by a Combination of Macrophages and Soluble Mediators Present in Age-Related Macular Degeneration

Purpose Retinal pigment epithelial (RPE) cells have an important role in the immune suppression associated with the immune privilege of the eye. Some aspects of this remain unclear and this study aimed to determine how RPE cells could influence the production of chemokines by T lymphocytes. Methods T lymphocytes, separated from peripheral blood of normal volunteers, and RPE cells, cultured from donor eyes, were cultured separately and together, either in contact or in transwells. Supernatants were analyzed for CCL3, CCL4, and soluble CD54 (sCD54) by ELISA. Blocking agents were used to determine which soluble mediators were involved. Results Coculture of RPE cells with activated lymphocytes resulted in a reduction in CCL3 and CCL4 production by lymphocytes, primarily by soluble mediators. Soluble CD54 was markedly increased on coculture of lymphocytes with RPE cells. Soluble CD54 reduced CCL3 and CCL4 production by RPE cells, and inhibition of CCL3 and CCL4 on coculture with RPE cells was reduced by anti-CD54. Blocking prostaglandin E2 (PGE2) abrogated the inhibition of CCL4, but not CCL3, by RPE cells. Blocking TGFβ and nitric oxide production had no effect. Conclusions RPE cells are able to down-regulate high levels of CCL3 and CCL4 production by T lymphocytes by using the soluble mediators sCD54 and PGE2. Reducing this production of CCL3 and CCL4 will dampen down the cascade effect and recruitment of more inflammatory cells, protecting the retina from an excessive immune response.

Regulation of T-lymphocyte CCL3 and CCL4 production by retinal pigment epithelial cells.

Reduced expression of CD200 and CD47 may be associated with development of age-related macular degeneration

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