bims-mideyd 2022-07-17 papers

Front Mol Neurosci. 2022 ;15 896786

Dimethyl Fumarate Blocks Tumor Necrosis Factor-Alpha-Driven Inflammation and Metabolic Rewiring in the Retinal Pigment Epithelium.

Daisy Y Shu, Scott I Frank, Tessa C Fitch, Margarete M Karg, Erik R Butcher, Emmanuella Nnuji-John, Leo A Kim, Magali Saint-Geniez.

The retinal pigment epithelium (RPE) acts as a metabolic gatekeeper between photoreceptors and the choroidal vasculature to maintain retinal function. RPE dysfunction is a key feature of age-related macular degeneration (AMD), the leading cause of blindness in developed countries. Inflammation is a key pathogenic mechanism in AMD and tumor necrosis factor-alpha (TNFα) has been implicated as a pro-inflammatory cytokine involved in AMD. While mitochondrial dysfunction has been implicated in AMD pathogenesis, the interplay between inflammation and cellular metabolism remains elusive. The present study explores how the pro-inflammatory cytokine, TNFα, impacts mitochondrial morphology and metabolic function in RPE. Matured human primary RPE (H-RPE) were treated with TNFα (10 ng/ml) for up to 5 days. TNFα-induced upregulation of IL-6 secretion and inflammatory genes (IL-6, IL-8, MCP-1) was accompanied by increased oxidative phosphorylation (OXPHOS) and reduced glycolysis, leading to an increase in cellular adenosine triphosphate (ATP) content. Transmission electron microscopy (TEM) revealed defects in mitochondrial morphology with engorged mitochondria and loss of cristae integrity following TNFα treatment. Pre-treatment with the anti-inflammatory drug, 80 μM dimethyl fumarate (DMFu), blocked TNFα-induced inflammatory activation of RPE (IL-6, IL-8, MCP-1, CFH, CFB, C3) and normalized their bioenergetic profile to control levels by regulating PFKFB3 and PKM2 gene expression. Furthermore, DMFu prevented TNFα-induced mitochondrial dysfunction and morphological anomalies. Thus, our results indicate that DMFu serves as a novel therapeutic avenue for combating inflammatory activation and metabolic dysfunction of RPE in AMD.

Keywords: age-related macular degeneration; glycolysis; inflammation; metabolism; mitochondria; oxidative phosphorylation; retinal pigment epithelium; tumor necrosis factor-alpha

DOI: https://doi.org/10.3389/fnmol.2022.896786

Exp Eye Res. 2022 Jul 11. pii: S0014-4835(22)00250-0. [Epub ahead of print] 109170

Cell culture models to study retinal pigment epithelium-related pathogenesis in age-related macular degeneration.

Kapil Bharti, Anneke I den Hollander, Aparna Lakkaraju, Debashish Sinha, David Williams, Silvia C Finnemann, Catherine Bowes Rickman, Goldis Malek, Patricia A D'Amore.

Age-related macular degeneration (AMD) is a disease that affects the macula - the central part of the retina. It is a leading cause of irreversible vision loss in the elderly. AMD onset is marked by the presence of lipid- and protein-rich extracellular deposits around the retinal pigment epithelium (RPE), a monolayer of polarized, pigmented epithelial cells located between the photoreceptors and the choroidal blood supply. Progression of AMD to the late nonexudative "dry" stage of AMD, also called geographic atrophy, is linked to progressive loss of areas of the RPE, photoreceptors, and underlying choriocapillaris leading to a severe decline in patients' vision. Differential susceptibility of macular RPE in AMD and the lack of an anatomical macula in most lab animal models has promoted the use of in vitro models of the RPE. In addition, the need for high throughput platforms to test potential therapies has driven the creation and characterization of in vitro model systems that recapitulate morphologic and functional abnormalities associated with human AMD. These models range from spontaneously formed cell line ARPE19, immortalized cell lines such as hTERT-RPE1, RPE-J, and D407, to primary human (fetal or adult) or animal (mouse and pig) RPE cells, and embryonic and induced pluripotent stem cell (iPSC) derived RPE. Hallmark RPE phenotypes, such as cobblestone morphology, pigmentation, and polarization, vary significantly between different models limiting their usability for investigating different aspects of AMD biology. Here the AMD Disease Models task group of the Ryan Initiative for Macular Research (RIMR) provides a summary of several currently used in vitro RPE models, historical aspects of their development, RPE phenotypes that are attainable in these models, their ability to model different aspects of AMD pathophysiology, and pros/cons for their use in the RPE and AMD fields. In addition, due to the burgeoning use of iPSC derived RPE cells, the critical need for developing standards for differentiating and rigorously characterizing RPE cell appearance, morphology, and function are discussed.

Keywords: ARPE19; Complement system; Organ-on-a-Chip; Primary cells; Retinal pigment epithelium; iPSC-RPE

DOI: https://doi.org/10.1016/j.exer.2022.109170

Front Immunol. 2022 ;13 929230

Can the cGAS-STING Pathway Play a Role in the Dry Eye?

Weijie Ouyang, Shoubi Wang, Jiaoyue Hu, Zuguo Liu.

Dry eye is one of the most common ocular surface diseases in the world and seriously affects the quality of life of patients. As an immune-related disease, the mechanism of dry eye has still not been fully elucidated. The cGAS-STING pathway is a recently discovered pathway that plays an important role in autoimmune and inflammatory diseases by recognizing dsDNA. As an important signal to initiate inflammation, the release of dsDNA is associated with dry eye. Herein, we focused on the pathophysiology of the immune-inflammatory response in the pathogenesis of dry eye, attempted to gain insight into the involvement of dsDNA in the dry eye immune response, and investigated the mechanism of the cGAS-STING pathway involved in the immune-inflammatory response. We further proposed that the cGAS-STING pathway may participate in dry eye as a new mechanism linking dry eye and the immune-inflammatory response, thus providing a new direction for the mechanistic exploration of dry eye.

Keywords: cGAS-STING pathway; dry eye; dsDNA; inflammation; innate immunity

DOI: https://doi.org/10.3389/fimmu.2022.929230

Biochem Pharmacol. 2022 Jul 11. pii: S0006-2952(22)00262-3. [Epub ahead of print] 115168

Treatment and Prevention of Pathological Mitochondrial Dysfunction in Retinal Degeneration and in Photoreceptor Injury.

Walter H Moos, Douglas V Faller, Ioannis P Glavas, David N Harpp, Natalia Kamperi, Iphigenia Kanara, Krishna Kodukula, Anastasios N Mavrakis, Julie Pernokas, Mark Pernokas, Carl A Pinkert, Whitney R Powers, Konstantina Sampani, Kosta Steliou, Constantin Tamvakopoulos, Demetrios G Vavvas, Robert J Zamboni, Xiaohong Chen.

Pathological deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and age-related chronic diseases, including those of genetic origin. Several of these diseases are rare, typically defined in the United States as an illness affecting fewer than 200,000 people in the U.S. population, or about one in 1,600 individuals. Vision impairment due to mitochondrial dysfunction in the eye is a prominent feature evident in numerous primary mitochondrial diseases and is common to the pathophysiology of many of the familiar ophthalmic disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma and retinopathy of prematurity - a collection of syndromes, diseases and disorders with significant unmet medical needs. Focusing on metabolic mitochondrial pathway mechanisms, including the possible roles of cuproptosis and ferroptosis in retinal mitochondrial dysfunction, we shed light on the potential of α-lipoyl-L-carnitine in treating eye diseases. α-Lipoyl-L-carnitine is a bioavailable mitochondria-targeting lipoic acid prodrug that has shown potential in protecting against retinal degeneration and photoreceptor cell loss in ophthalmic indications.

Keywords: Cuproptosis; ferroptosis; macular degeneration; mitochondrial disease; ophthalmology; photoreceptor cells; rare diseases; retinal disease; therapeutics; α-lipoic acid

DOI: https://doi.org/10.1016/j.bcp.2022.115168