bims-mideyd 2023-10-15 papers

bioRxiv. 2023 Sep 29. pii: 2023.09.27.559733. [Epub ahead of print]

Replenishing Age-Related Decline of IRAK-M Expression in Retinal Pigment Epithelium Attenuates Outer Retinal Degeneration.

Unchecked, chronic inflammation is a constitutive component of age-related diseases, including age-related macular degeneration (AMD). Here we identified interleukin-1 receptor-associated kinase (IRAK)-M as a key immunoregulator in retinal pigment epithelium (RPE) that declines with age. Rare genetic variants of IRAK-M increased the likelihood of AMD. IRAK-M expression in RPE declined with age or oxidative stress and was further reduced in AMD. IRAK-M-deficient mice exhibited increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M disrupted RPE cell homeostasis, including compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of AAV-expressing IRAK-M rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in IRAK-M- deficient mice. Our data support that replenishment of IRAK-M expression may redress dysregulated pro-inflammatory processes in AMD, thereby treating degeneration.
One Sentence Summary: IRAK-M is a protective molecule and promising therapeutic target for macular degeneration.

DOI: https://doi.org/10.1101/2023.09.27.559733

Discov Med. 2023 10;35(178): 796-804

TLR4 Inhibition Protects against Retinal Ganglion Cell Damage in Rats with Chronic Ocular Hypertension.

Zhongjing Lin, Li Ru, Hongliang Wang, Ke Mao.

BACKGROUND: This study aims to investigate the protective effect of Toll-like receptor 4 (TLR4) inhibitor Resatorvid (TAK-242) on retinal ganglion cells (RGCs) in a chronic ocular hypertension (COH) rat model, as well as to explore the potential involved mechanisms.
METHODS: COH model was built up in rats with a single intracameral administration of cross-linking hydrogel. The expression levels of TLR4, NLR family pyrin domain containing 3 (NLRP3), microglial activation and pro-inflammatory cytokines were evaluated in COH retinas and COH retinas treated with TAK-242 using immunofluorescence staining and Western blot. Additionally, retrograde labeling and neuronal nuclear protein (NeuN) staining were performed to count RGCs.
RESULTS: Activated microglia and increased TLR4 expression were observed in the retinas of COH rats. This was accompanied by upregulated expressions of NLRP3, tumor necrosis factor alpha (TNF-α), cytokine interleukin-1β (IL-1β) and Interleukin-6 (IL-6). Intravitreal injection of TAK-242 promoted the survival of RGCs by attenuating microglial activation, interfering with the TLR4-NLRP3 pathway and regulating pro-inflammatory cytokines.
CONCLUSIONS: Targeting TLR4 inhibition could be a potential therapeutic strategy to protect RGCs from COH damage.

Keywords: chronic ocular hypertension; microglial activation; retinal ganglion cells

DOI: https://doi.org/10.24976/Discov.Med.202335178.74

J Fr Ophtalmol. 2023 Oct 06. pii: S0181-5512(23)00144-4. [Epub ahead of print]

Antioxidative effects of ghrelin on human trabecular meshwork cells.

R Wang, Y Wang, Y Qin, H Wei.

Glaucoma is a group of neurodegenerative diseases characterized by loss of retinal ganglion cells and visual field defects and is one of the major causes of irreversible blindness worldwide. Primary open-angle glaucoma (POAG) is one of the classifications of glaucoma. Oxidative stress in trabecular reticulated cells is one of the possible mechanisms of the development of glaucoma. At present, there is still a lack of effective methods to treat glaucoma. Ghrelin is characterized by its wide distribution and high potency and has anti-inflammatory, antioxidant, and anti-apoptotic effects, which may be beneficial in the treatment of glaucoma. In this study, we investigated whether ghrelin can protect human trabecular meshwork cells (HTMCs) from oxidative damage induced by hydrogen peroxide (H2O2), as well as the possible mechanism of action. CCK8 and flow cytometry results revealed that treatment of HTMCs with ghrelin showed a dose-dependent protective effect against H2O2-induced damage. Ghrelin significantly decreased the rate of apoptosis and levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased the level of superoxide dismutase (SOD) and catalase (CAT) in HTMCs. The difference was statistically significant compared with the H2O2 group. Ghrelin activated Nrf2/HO-1/NQO-1 signaling pathways and decreased HIF-1α level in H2O2-injured HTMCs as shown on qPCR and Western blot. In conclusion, ghrelin can protect HTMCs from oxidative damage induced by H2O2 and reduce apoptosis in HTMCs, which can be a new approach to treating POAG. The underlying therapeutic mechanism may be related to Nrf2/HO-1/NQO-1 signaling pathways and HIF-1α.

Keywords: Antioxidation; Antioxydants; Cellules trabéculaires humaines; Ghrelin; Ghréline; Glaucome primaire à angle ouvert (GPAO); Human trabecular meshwork cells; Oxidative stress; Primary open-angle glaucoma; Stress oxydant

DOI: https://doi.org/10.1016/j.jfo.2022.11.023

Front Ophthalmol (Lausanne). 2023 ;pii: 1217137. [Epub ahead of print]3

Astrocytes of the eye and optic nerve: heterogeneous populations with unique functions mediate axonal resilience and vulnerability to glaucoma.

Paul F Cullen, Daniel Sun.

The role of glia, particularly astrocytes, in mediating the central nervous system's response to injury and neurodegenerative disease is an increasingly well studied topic. These cells perform myriad support functions under physiological conditions but undergo behavioral changes - collectively referred to as 'reactivity' - in response to the disruption of neuronal homeostasis from insults, including glaucoma. However, much remains unknown about how reactivity alters disease progression - both beneficially and detrimentally - and whether these changes can be therapeutically modulated to improve outcomes. Historically, the heterogeneity of astrocyte behavior has been insufficiently addressed under both physiological and pathological conditions, resulting in a fragmented and often contradictory understanding of their contributions to health and disease. Thanks to increased focus in recent years, we now know this heterogeneity encompasses both intrinsic variation in physiological function and insult-specific changes that vary between pathologies. Although previous studies demonstrate astrocytic alterations in glaucoma, both in human disease and animal models, generally these findings do not conclusively link astrocytes to causative roles in neuroprotection or degeneration, rather than a subsequent response. Efforts to bolster our understanding by drawing on knowledge of brain astrocytes has been constrained by the primacy in the literature of findings from peri-synaptic 'gray matter' astrocytes, whereas much early degeneration in glaucoma occurs in axonal regions populated by fibrous 'white matter' astrocytes. However, by focusing on findings from astrocytes of the anterior visual pathway - those of the retina, unmyelinated optic nerve head, and myelinated optic nerve regions - we aim to highlight aspects of their behavior that may contribute to axonal vulnerability and glaucoma progression, including roles in mitochondrial turnover and energy provisioning. Furthermore, we posit that astrocytes of the retina, optic nerve head and myelinated optic nerve, although sharing developmental origins and linked by a network of gap junctions, may be best understood as distinct populations residing in markedly different niches with accompanying functional specializations. A closer investigation of their behavioral repertoires may elucidate not only their role in glaucoma, but also mechanisms to induce protective behaviors that can impede the progressive axonal damage and retinal ganglion cell death that drive vision loss in this devastating condition.

Keywords: astrocyte heterogeneity; astrocyte metabolism; gap junctions; glaucoma; mitochondria; neurodegeneration; optic nerve head astrocytes; reactive astrocytes

DOI: https://doi.org/10.3389/fopht.2023.1217137

DNA Cell Biol. 2023 Oct 11.

The Molecular Mechanisms Involved in Axonal Degeneration and Retrograde Retinal Ganglion Cell Death.

Zhaoyang Zuo, Ziyuan Zhang, Siming Zhang, Bin Fan, Guangyu Li.

Axonal degeneration is a pathologic change common to multiple retinopathies and optic neuropathies. Various pathologic factors, such as mechanical injury, inflammation, and ischemia, can damage retinal ganglion cell (RGC) somas and axons, eventually triggering axonal degeneration and RGC death. The molecular mechanisms of somal and axonal degeneration are distinct but also overlap, and axonal degeneration can result in retrograde somal degeneration. While the mitogen-activated protein kinase pathway acts as a central node in RGC axon degeneration, several newly discovered molecules, such as sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 and nicotinamide mononucleotide adenylyltransferase 2, also play a critical role in this pathological process following different types of injury. Therefore, we summarize the types of injury that cause RGC axon degeneration and retrograde RGC death and important underlying molecular mechanisms, providing a reference for the identification of targets for protecting axons and RGCs.

Keywords: axonal degeneration; mitogen-activated protein kinase; nicotinamide mononucleotide adenylyltransferase; retinal ganglion cell; retrograde cell death; somal degeneration

DOI: https://doi.org/10.1089/dna.2023.0180

J Control Release. 2023 Oct 09. pii: S0168-3659(23)00662-4. [Epub ahead of print]

Schwann cell-derived extracellular vesicles as a potential therapy for retinal ganglion cell degeneration.

Senmiao Zhu, Lili Chen, Min Wang, Jing Zhang, Gang Chen, Yinghao Yao, Shihan Song, Tong Li, Shenglan Xu, Zhonghao Yu, Bingyan Shen, Duogang Xu, Zai-Long Chi, Wencan Wu.

Optic neuropathy is the leading cause of irreversible blindness and is characterized by progressive degeneration of retinal ganglion cells (RGCs). Several studies have demonstrated that transplantation of Schwann cells (SCs) is a promising candidate therapy for optic neuropathy and that intravitreally transplanted cells exert their effect via paracrine actions. Extracellular vesicle (EV)-based therapies are increasingly recognized as a potential strategy for cell replacement therapy. In this study, we aimed to investigate the neuroprotective and regenerative effects of SC-EVs following optic nerve injury. We found that SC-EVs were internalized by RGCs in vitro and in vivo without any transfection reagents. Intriguingly, SC-EVs significantly enhanced the survival and axonal growth of primary RGCs in a coculture system. In a rat optic nerve crush model, SC-EVs mitigated RGC degeneration, prevented RGC loss, and preserved the thickness of the ganglion cell complex, as demonstrated by the statistically significant improvement in RGC counts and thickness measurements. Mechanistically, SC-EVs activated the cAMP-response element binding protein (CREB) signaling pathway and regulated reactive gliosis in ONC rats, which is crucial for RGC protection and axonal regeneration. These findings provide novel insights into the neuroprotective and regenerative properties of SC-EVs, suggesting their potential as a cell-free therapeutic strategy and natural biomaterials for neurodegenerative diseases of the central nervous system.

Keywords: CREB signaling pathway; Natural biomaterials; Optic neuropathy; Retinal ganglion cells; Schwann cells; Small extracellular vesicles

DOI: https://doi.org/10.1016/j.jconrel.2023.10.012

J Clin Med. 2023 Sep 27. pii: 6229. [Epub ahead of print]12(19):

Updates on Emerging Interventions for Autosomal Recessive ABCA4-Associated Stargardt Disease.

Liang Wang, Serena M Shah, Simran Mangwani-Mordani, Ninel Z Gregori.

Autosomal recessive Stargardt disease (STGD1) is an inherited retinal degenerative disease associated with a mutated ATP-binding cassette, subfamily A, member 4 (ABCA4) gene. STGD1 is the most common form of juvenile macular degeneration with onset in late childhood to early or middle adulthood and causes progressive, irreversible visual impairment and blindness. No effective treatment is currently available. In the present article, we review the most recent updates in clinical trials targeting the management of STGD1, including gene therapy, small molecule therapy, and stem cell therapy. In gene therapy, dual adeno-associated virus and non-viral vectors have been successful in delivering the human ABCA4 gene in preclinical studies. For pharmaceutical therapies ALK-001, deuterated vitamin A shows promise with preliminary data for phase 2 trial, demonstrating a decreased atrophy growth rate after two years. Stem cell therapy using human pluripotent stem cell-derived retinal pigment epithelium cells demonstrated long-term safety three years after implantation and visual acuity improvements in the first two years after initiation of therapy. Many other treatment options have ongoing investigations and clinical trials. While multiple potential interventions have shown promise in attenuating disease progression, further exploration is necessary to demonstrate treatment safety and efficacy.

Keywords: ABCA4; Stargardt disease; adeno-associated viral vectors; deuterated vitamin A; emixustat; gene therapy; human embryonic stem cells; stem cell therapy; visual cycle modulators

DOI: https://doi.org/10.3390/jcm12196229