bims-mideyd 2025-05-25 papers

Lab Invest. 2025 May 21. pii: S0023-6837(25)00107-2. [Epub ahead of print] 104197

Aryl hydrocarbon receptor deficiency upregulates intercellular adhesion molecule 1 in retinal pigment epithelial cells and contributes to retinal inflammation.

Tsung-Min Yang, Te-Chao Fang, Yu-Cheng Lee, Chen-Chen Lee, Yen-Ju Chan, Ida Fitriana, Yu-Wen Cheng, Ching-Hao Li.

Retinal pigment epithelium (RPE) cells, located between the photoreceptors and choroid, play a crucial role in maintaining retinal health and function. They act as immunosuppressive barriers, preventing immune cell infiltration from the choroid. Retinal inflammation contributes to the development of various ocular diseases. The aryl hydrocarbon receptor (AHR) is a well-established ligand-dependent transcription factor that mediates potent anti-inflammatory signals following ligand binding. AHR expression is notably reduced under several conditions that negatively affect the retina. We hypothesized that AHR protein loss may impairs RPE cell function, shifting them toward a pro-inflammatory phenotype. In this study, we investigated the pro-inflammatory pathways activated by AHR knockout (AHR-KO) and examined associated retinal phenotypic changes in AHR-KO mice. Our findings suggest that AHR deficiency may enhance the activity of αvβ3-integrin, extracellular signal-regulated kinases (ERK1/2), and p65 subunit of nuclear factor kappa B (NF-κB), leading to an upregulation of intercellular adhesion molecule 1 (ICAM1) and promoting monocyte adhesion in vitro. Introducing an AHR-green fluorescent protein into AHR-KO RPE cells or pre-treating the cells with pharmacological inhibitors targeting αvβ3 (cycloRGDfk), focal adhesion kinase (PF573228), phospholipase C (U73122), ERK1/2 (U0126), and NF-κB (Bay11-7082) prevented ICAM1 induction in AHR-KO RPE cells. These results suggest that the pro-inflammatory pathway is driven by AHR deficiency. In AHR-KO mice, retinal tissues showed ICAM1 accumulation, microglial activation, and migration, indicating chronic retinal inflammation due to AHR deficiency. These mice also displayed early-onset electroretinogram degeneration. Collectively, our data support the protective role of AHR in maintaining RPE cell physiology and retinal health.

Keywords: aryl hydrocarbon receptor; intercellular adhesion molecule 1; retinal inflammation; retinal pigment epithelium; αvβ3-integrin

DOI: https://doi.org/10.1016/j.labinv.2025.104197

Front Cell Dev Biol. 2025 ;13 1595121

Protein misfolding and mitochondrial dysfunction in glaucoma.

Arunkumar Venkatesan, Audrey M Bernstein.

Glaucoma is a leading cause of irreversible blindness worldwide. Elevated intraocular pressure caused by restricted outflow of the aqueous humor leads to the degeneration of retinal ganglion cells (RGCs) and their axons. Emerging evidence suggests that pathological mechanisms relating to protein folding and mitochondrial dysfunction are significant factors in the disease onset of different types of open-angle glaucoma. In this review, we discuss these defects in three distinct types of open-angle glaucoma: primary open-angle glaucoma (POAG), normal tension glaucoma (NTG), and exfoliation glaucoma (XFG). Genetic mutations linked to the previously mentioned open-angle glaucoma, including those in myocilin (MYOC), optineurin (OPTN), and lysyl oxidase 1 (LOXL1), disrupt protein folding and homeostasis, leading to endoplasmic reticulum stress, activation of the unfolded protein response and impaired autophagic protein degradation. These factors contribute to trabecular meshwork and retinal ganglion cell apoptosis. In addition to protein folding defects, mitochondrial dysfunction is also associated with the progression of trabecular meshwork damage and the death of RGCs. Factors such as oxidative stress, an altered mitochondrial fission-fusion balance, and mitophagy dysregulation make RGCs vulnerable and contribute to optic nerve degeneration. The crosstalk between protein folding and mitochondrial defects in glaucoma underscores the complexity of disease pathogenesis and offers potential targets for therapeutic intervention. Strategies aimed at restoring protein homeostasis, enhancing mitochondrial function, and mitigating cellular stress responses hold promise for neuroprotection in glaucoma.

Keywords: NTG; POAG; XFG; autophagy; er stress; glaucoma; mitochondrial dysfunction; upr

DOI: https://doi.org/10.3389/fcell.2025.1595121

Adv Sci (Weinh). 2025 May 21. e2505359

PHOSPHO1 Suppresses Ferroptosis in Retinal Pigment Epithelial Cells by Reducing the Levels of Phosphatidylethanolamine Molecular Species.

Iron-induced lipid peroxidation of phosphatidylethanolamine (PE) species is a key driver of ferroptosis in retinal pigment epithelial (RPE) cells, a process closely associated with age-related macular degeneration (AMD). The previous studies have demonstrated that induced retinal pigment epithelial (iRPE) cells generated by transcription factor-mediated reprogramming exhibit superior therapeutic efficacy in treating AMD. In this study, it is found that these iRPE cells are resistant to ferroptosis and further identified phosphoethanolamine/phosphocholine phosphatase 1 (PHOSPHO1) as a critical regulator underlying ferroptosis resistance. Mechanistically, PHOSPHO1 inhibits ferroptosis through two distinct mechanisms. First, it reduces PE levels in the endoplasmic reticulum, thereby limiting PE-derived lipid peroxidation. Second, it suppresses autophagy and ferritinophagy, leading to a reduction in intracellular free iron accumulation. Experiments using an in vivo rat model confirm that PHOSPHO1 effectively protects RPE cells from ferroptotic damage. These findings highlight PHOSPHO1 as a potential therapeutic target for AMD, providing insights into novel ferroptosis-based intervention strategies.

Keywords: age‐related macular degeneration; ferroptosis; phosphatidylethanolamine; phosphoethanolamine/phosphocholine phosphatase 1; retinal pigment epithelial cells

DOI: https://doi.org/10.1002/advs.202505359

Invest Ophthalmol Vis Sci. 2025 May 01. 66(5): 30

Protein Acetylation in Age-Related Macular Degeneration: Mechanisms, Roles, and Therapeutic Perspectives.

Tianyi Luo, Cunzi Li, Lan Zhou, Hongyan Sun, Ming Ming Yang.

Age-related macular degeneration (AMD) is a top cause of severe vision loss and blindness in older adults globally. This multifactorial disease arises from genetic, environmental, and age-related factors. Protein acetylation modification plays a key role in AMD progression through both epigenetic and non-epigenetic pathways. This review comprehensively discusses the multidimensional impacts of protein acetylation in AMD, particularly its dynamic regulation of angiogenesis, oxidative stress, inflammatory responses, and cellular senescence. Recent evidence shows that histone acetylation modification inhibits choroidal neovascularization (CNV) formation by regulating vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF-1α) expression, while upregulating the complement inhibitor clusterin to maintain Bruch's membrane integrity. Additionally, the NAD+-dependent deacetylase SIRT1 modulates the deacetylation of transcription factors such as PGC-1α, NF-κB, and FOXO3, enhancing mitochondrial antioxidant function and suppressing inflammatory cascades to disrupt the vicious cycle of oxidative stress and chronic inflammation. In terms of cellular senescence, histone hypoacetylation and hyperacetylation of non-histone proteins (e.g., p53, E2F1) jointly cause retinal pigment epithelial (RPE) cell-cycle arrest and autophagy imbalance, accelerating AMD progression. Genetic evidence further reveals subtype-specific expression changes and epigenetic regulatory mechanisms of histone deacetylases (HDACs), such as HDAC11 and HDAC1/3, in AMD. This article explores the clinical significance of these findings and proposes a novel combined therapeutic strategy. It involves synergistically targeting acetylation homeostasis with HDAC inhibitors (e.g., TSA, AN7) and SIRT1 activators while inhibiting abnormal angiogenesis, repairing metabolic disorders, and restoring autophagy function. This dual-targeting approach may overcome current anti-VEGF therapy limitations and open new precision management avenues for AMD.

DOI: https://doi.org/10.1167/iovs.66.5.30

FASEB J. 2025 May 31. 39(10): e70671

Stromal-Like Cells and Retinal Pigment Epithelium Modulate Choroidal Sprouting Through Galectin-1-Dependent and Independent Pathways.

Magali E Ridano, Christin Hanke-Gogokhia, Guillermo L Lehmann, Paulo S Caceres, Maria V Vaglienti, Danilo Ceschin, Ryan Schreiner, Diego O Croci, Carlos Torroja-Fungairiño, Enrique Rodriguez-Boulan, Ignacio Benedicto, Gabriel A Rabinovich, María C Sánchez.

Outer retinal function depends on two supporting tissues: the retinal pigment epithelium (RPE) and the choroid. Limited molecular information is available on the intercellular networks that sustain RPE/choroid tissue in both healthy and pathological states. Galectin-1 (Gal1), a β-galactoside-binding lectin, has recently emerged as a key regulator of angiogenesis and a potential therapeutic target in vascular pathologies, including age-related macular degeneration. Here, we studied the expression of Gal1 in the outer retina and its regulatory role in the RPE/choroid under physiological and pathological conditions. Our findings indicate that Gal1 is predominantly associated with stromal cells in the RPE/choroid. In Gal1-deficient (Lgals1-/-) mice, the RPE/choroid ultrastructure and gene expression profiles were altered, and choroidal explants exhibited reduced sprouting compared to those of wild-type mice. Consistently, recombinant Gal1 promoted choroidal sprouting under hypoxic conditions, and stromal-like cells modulated pro-angiogenic and antiangiogenic gene expression in vitro under pathological conditions. Interestingly, Gal1 was also expressed by the RPE, with apical secretion under normoxia that shifted toward a basolateral phenotype under hypoxia. These findings identify stromal-like cells and RPE as key sources of Gal1 in the choroid, highlighting its distinct roles in maintaining RPE/choroid homeostasis in healthy or pathological microenvironments.

Keywords: Galectin‐1; age‐related macular degeneration; angiogenesis; hypoxia; inflammation; ocular physiological processes

DOI: https://doi.org/10.1096/fj.202403181R