bims-mideyd 2025-07-20 papers

Invest Ophthalmol Vis Sci. 2025 Jul 01. 66(9): 44

C5a-Induced Autophagy Dysfunction Promotes Choroidal Neovascularization Through the ROS-Inflammatory Pathway.

Yong Du, Lujia Feng, Jihong Tang, Xi Qin, Bingyu Bai, Liang Liang.

Purpose: Age-related macular degeneration (AMD) is the leading cause of blindness in aging populations. C5a is the primary component of drusen and exerts a pivotal role in AMD, facilitating its progression. In the present research, we explored how C5a exacerbates AMD pathogenesis and its interplay with autophagic pathways, mitochondrial reactive oxygen species (ROS), and proinflammatory cytokines.
Methods: Human retinal pigment epithelial (ARPE-19) cells were exposed to recombinant C5a. Autophagy was modulated using rapamycin or 3-MA, and ROS dynamics were perturbed with DPI or rotenone. Autophagy markers (LC3-II, Beclin-1, p62/SQTSM1) were analyzed via Western blot. Mitochondrial ROS levels were quantified using MitoSOX Red, while cytokine secretion (VEGF, MCP-1, IL-6, and IL-8) was measured by ELISA. C57BL/6 mice were utilized to model choroidal neovascularization (CNV), a prevalent subtype of AMD, which was induced by laser photocoagulation.
Results: C5a stimulation significantly increased LC3-II, Beclin-1, and p62/SQTSM1. The cytokine secretion (VEGF, MCP-1, IL-6, and IL-8), ROS, and the areas in laser-induced CNV were significantly enlarged after C5a treatment. Autophagy activator significantly downregulated the cytokine secretion (VEGF, MCP-1, IL-6, and IL-8), ROS, and the areas in laser-induced CNV. ROS inhibitors can markedly diminish IL-6, IL-8, MCP-1, and VEGF, as well as the progression of CNV.
Conclusions: Our results suggest that C5a induced the dysfunction of autophagy and increased the mitochondrial ROS, as well as the mitochondrial ROS-driven cytokine release that fuels CNV formation.

DOI: https://doi.org/10.1167/iovs.66.9.44

Aging Cell. 2025 Jul 15. e70163

Age-Dependent Histone Deacetylase 3 Regulation by βA3/A1-Crystallin and Inositol Hexaphosphate in Retinal Pigmented Epithelial Cells Reveals a Novel Pathway in Age-Related Macular Degeneration.

Sujan Chatterjee, Sayan Ghosh, Zachary Sin, Vishnu Suresh Babu, Loretta Viera Preval, Emily Davis, Nguyen Tran, Sridhar Bammidi, Pooja Gautam, Stacey Hose, Yuri Sergeev, Miguel Flores-Bellver, Kevin Ritter, Henning J Jessen, Issam Al Diri, Debasish Sinha, Prasun Guha.

Age-related macular degeneration (AMD), a leading cause of vision loss affecting retinal pigment epithelial (RPE) cells, remains largely unexplained by current genome-wide association studies (GWAS) risk variants. Our research on Cryba1, encoding βA3/A1-crystallin protein, reveals its crucial role in RPE cell function via a novel epigenetic mechanism, also evident in human atrophic AMD samples. Loss of Cryba1 in mouse RPE cells triggers epigenetic changes by reducing histone deacetylase 3 (HDAC3) activity through two mechanisms. First, Cryba1 depletion reduces inositol polyphosphate multikinase (IPMK) expression, which potentially reduces inositol hexakisphosphate (InsP6) generation since IPMK's kinase activity is essential for producing InsP4 and InsP5 as precursors to InsP6. Since InsP4, InsP5, or InsP6 is crucial for HDAC3's interaction with the corepressor's DAD domains, reduced IPMK expression in Cryba1-depleted cells likely diminishes the HDAC3-DAD interaction, leading to a reduction in HDAC3's activity. Second, reduced βA3/A1 protein in Cryba1-deficient cells impairs HDAC3's interaction with casein kinase 2 (CK2), resulting in decreased HDAC3 phosphorylation. Collectively, this increases H3K27 acetylation at the RET promoter region, likely enhancing the transcription of RET, a receptor tyrosine kinase critical for cell survival. Although RET is transcriptionally increased, Cryba1 loss disrupts its protein maturation, causing immature RET protein accumulation. This triggers age-dependent endoplasmic reticulum (ER) stress, potentially contributing to the pathogenesis of AMD. Interestingly, although Cryba1 is not identified as an AMD-linked variant in current GWAS, its loss may be linked to AMD mechanisms. These findings underscore the potential of gene-agnostic and epigenetic therapeutic strategies for treating AMD.

Keywords: HDAC3; atrophic age‐related macular degeneration; casein kinase II (CK2); endoplasmic reticulum stress; histone acetylation; inositol hexaphosphate; inositol polyphosphate multikinase; βA3/A1‐crystallin

DOI: https://doi.org/10.1111/acel.70163

Proc Natl Acad Sci U S A. 2025 Jul 22. 122(29): e2503191122

Glycolipids implicated as mediators of clinically visible retinal pigment epithelial migration in age-related macular degeneration.

Zhen Wang, David M G Anderson, Jeffrey D Messinger, Christine A Curcio, Kevin L Schey.

The retinal pigment epithelium (RPE) is the metabolic gatekeeper to the photoreceptors, thus playing many essential roles in healthy vision. Under certain conditions, RPE cells may transdifferentiate and migrate from the RPE layer. Ectopic RPE cells are potential signal sources for hyperreflective foci, prominent clinically visible biomarkers in age-related macular degeneration, which causes central vision loss globally. Applying multiple imaging modalities including ex vivo optical coherence tomography, autofluorescence microscopy, and imaging mass spectrometry (IMS) to human retina tissue, we compared lipid profiles in ectopic and orthotopic RPE cells. Our results showed that ectopic RPE cells share some molecular signatures with normal RPE cells as revealed through autofluorescence imaging and IMS. In both orthotopic and ectopic RPE cells, IMS detected phosphatidylglycerol, PG 36:2, and several triacylglycerols containing long-chain fatty acids. GM3 gangliosides (40:1, 42:1, and 42:2) were also detected in ectopic RPE cells with differences in abundance in different populations of ectopic RPE cells. Lactosylceramide (LacCer 44:5) and glucosylceramide (GlcCer 44:5) were found exclusively in ectopic RPE cells. In contrast, ectopic RPE did not exhibit signals of phosphatidylinositols (PI) (PI32:0, PI32:1, PI34:1, and PI34:2) normally detected in RPE cells. Near-single-cell resolution IMS results suggest that RPE transdifferentiation, with loss of normal functions and gain of new functions like migration, may be linked to altered metabolism of glycosphingolipids and PIs.

Keywords: age-related macular degeneration; imaging mass spectrometry; retinal pigment epithelium

DOI: https://doi.org/10.1073/pnas.2503191122

Aging Cell. 2025 Jul 13. e70161

Senescence Alters Antimicrobial Peptide Expression and Induces Amyloid-β Production in Retinal Pigment Epithelial Cells.

Jian Liu, Caijiao Yi, Jinyan Qi, Xuexue Cui, Xiangling Yuan, Wen Deng, Mei Chen, Heping Xu.

Age-related retinal degeneration, such as diabetic retinopathy and age-related macular degeneration, are major causes of blindness in modern society. Recent studies suggest that dysbiosis and intraocular translocation of bacteria from the blood circulation are critically involved in retinal degeneration. We hypothesise that the blood-retinal barrier (BRB) cells can protect the neuroretina from blood-borne pathogens by producing antimicrobial peptides (AMPs). The antimicrobial activity may decline during ageing, putting the retina at risk of low-degree chronic inflammation and degeneration. Here, we found that the retinal pigment epithelial (RPE) cells, which form the outer BRB, express a variety of AMPs/AMP precursors, including APP, RARRES2, FAM3A, HAMP, CAMP, GNLY, and PI3. Senescent RPE cells expressed lower levels of APP and RARRES2 mRNA, accompanied by increased intracellular retention of E. coli in a bactericidal assay. Silencing APP, not RARRES2, with shRNA reduced the antibacterial activity of RPE cells. Senescent RPE cells had lower levels of α-secretase and higher levels of β-secretase (BACE1) and γ-secretase (PS1), accompanied by reduced soluble APPα and increased amyloid beta (Aβ) production, particularly the Aβ42 isoform. Eyes from aged donors showed a higher Aβ accumulation within RPE cells. Our results suggest that while RPE cells possess antimicrobial activity, this ability declines with age and is impaired in senescent cells. The impaired antimicrobial activity and augmented Aβ deposition in senescent RPE cells may contribute to age-related retinal para-inflammation and neurodegeneration.

Keywords: ageing; blood‐retinal barrier; immune regulation; infectious; microbiota; para‐inflammation; retinal degeneration

DOI: https://doi.org/10.1111/acel.70161