Glaucoma is the major cause of irreversible blindness in the world characterized by progressive retinal neurodegeneration, in which local inflammation in retina is involved in persistent loss of retinal ganglion cells (RGCs). In order to explore whether aryl hydrocarbon receptor (AhR) and its agonists tryptophan metabolites are involved in the development of glaucoma, we collected serum and retinas from non-glaucoma controls and patients with glaucoma. Results showed altered serum tryptophan metabolism and reduced retinal AhR expression in glaucoma patients. We also showed intraperitoneally injection of tryptophan metabolite 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) down-regulated retinal local inflammation and protected RGC apoptosis from retinal ischemia/reperfusion (IR) injury via AhR activation. We further revealed that ITE could inhibit inflammation in BV2 microglia and alleviate the neurotoxicity of microglial conditioned medium to RGCs under IR. Finally, we illustrated the possible mechanism that ITE limited ERK and NFκB dependent microglial inflammation. In summary, these findings suggest the critical role of tryptophan metabolism and retinal AhR signaling in modulating local inflammation mediated by microglia in glaucoma, and provide a novel avenue to targeting the intrinsically altered AhR signaling resulted from disturbed tryptophan metabolism for glaucoma treatment.

Role of astrocyte polarization in glaucoma, a neurodegenerative disease, has not been fully explored. In this review, we first describe the characteristics of astrocyte astrogliosis in glaucoma, including morphological, molecular, proliferative and functional changes. We then summarize understanding of astrocyte polarization in other diseases, and show that A1 astrocytes are involved in the death of retinal ganglion cells in glaucoma, and that their neurotoxins kill only damaged retinal ganglion cells. Based on this, we propose new interesting conjecture on astrocyte polarization in glaucoma: (1) That the neurotoxin from A1 astrocytes is a product of the complement system (membrane-attacking complex), since this system is known to mediate synaptic elimination and the C3 expression is clearly increased in A1 astrocytes; (2) that reactive scar-forming astrocytes in the optic nerve head may be classified as A2 astrocytes since their ablation leads to a worse prognosis in glaucoma. Finally, current therapeutic research progress on astrocyte polarization in other diseases is also addressed. Regulation of astrocyte polarization can be achieved by extracellular microglia-related and intracellular pathways. Reduced A1 or increased A2 astrocytes can rescue the nerve. For example, glucagon-like peptide-1 receptor agonist rescues retinal ganglion cells by reducing A1 astrocytes via the extracellular microglia-related pathway in an ocular hypertension model, suggesting that regulation of astrocyte polarization as a therapeutic target in glaucoma is feasible....

As the important barrier of intraocular tissue, cornea is easy to suffer various kinds of injuries. Among them, acute alkali burn is a thorny ophthalmic emergency event, which can lead to corneal persistent epithelial defects, ulcers, and even perforation. Ferroptosis, a mode of regulatory cell death, has been found to play a key role in the process of corneal alkali burn, of which lipid peroxidation and intracellular iron levels are considered to be the possible therapeutic targets. To seek new effective treatments, the study herein focused on the occurrence of oxidative stress and ferroptosis in corneal alkali burn, exploring the role of phytic acid (PA), a natural small molecule with both antioxidant and iron chelating capacity, in the repair of corneal epithelial injury. The in vivo therapeutic results showed that PA eyedrops treatment promoted the recovery of corneal morphology and function, and in vitro experiments proved that PA prompted the repair of oxidative stress induced-corneal epithelial injury through ferroptosis inhibition. In addition, better drug treatment effect could be achieved through hydrogel delivery and sustained release, and our in vivo experiments showed the superior therapeutic effects of PA delivered by PVA hydrogels with larger molecular weights on corneal injury. In summary, this study demonstrated the excellent effect of natural small molecule PA with antioxidant and high efficiency chelating ferrous ions on ferroptosis inhibition, and showed the outstanding application prospect of PVA/PA hydrogels in the treatment of corneal epithelial injury.

Gut microbiota has emerged as a promising therapeutic target for neurodegenerative disorders through regulation of neuroinflammatory responses, while its role in optic nerve degeneration remains incompletely characterized. This study elucidates the neuroprotective role of gut microbiota derived tryptophan metabolites in glaucoma through gut-eye communication and inhibition of microglia-mediated neuroinflammation. Gut microbiota profiling (16 S rRNA sequencing) and serum indoleacetic acid (IAA) quantification were performed in glaucoma patients versus controls. Microbiota–metabolite relationships were further validated through fecal microbiota transplantation (FMT). The neuroprotective and anti-neuroinflammatory effect of Bacteroides fragilis (B. fragilis) and IAA was assessed in both microbead-induced ocular hypertension mice model and in vitro BV-2 microglial cell inflammation model via immunofluorescence, qPCR, Western blot and mice behavioral assays. To explore the underlying mechanisms, retinal transcriptomics and microglia-neuron co-cultures were also employed. Glaucoma patients exhibited gut dysbiosis characterized by depleted tryptophan-metabolizing bacteria (B. fragilis, Bacteroides thetaiotaomicron, Anaerostipes hadrus) and reduced serum IAA levels. Mice receiving FMT from glaucoma patients exhibited lower systemic IAA levels. In in vivo and in vitro models, B. fragilis or IAA restored AhR activation, suppressed inflammation by inhibiting microglial activation and the release of pro-inflammatory mediators throughout the retina, reduced retinal ganglion cells (RGCs) loss and preserved visual function. Mechanistically, IAA attenuated RAGE/NF-κB pathway activation via AhR-dependent signaling, conferring neuroprotection. Our study proposes a novel AhR-mediated gut microbiota-eye axis in glaucoma pathogenesis and demonstrates that IAA serves as an effective neuroprotective strategy with clinical potential for managing RGCs neurodegeneration.

Tarsal plate regeneration has always been a challenge in the treatment of eyelid defects. The commonly used clinical treatments such as hard palate mucosa grafts cannot achieve satisfactory repair effects. Tissue engineering has been considered as a promising technology. However, tarsal plate tissue engineering is difficult to achieve due to its complex structure and lipid secretion function. Three-dimensional (3D) printing technology has played a revolutionary role in tissue engineering because it can fabricate complex scaffolds through computer aided design (CAD). In this study, it was novel in applying 3D printing technology to the fabrication of tarsal plate scaffolds using poly-caprolactone (PCL). The decellularized matrix of adipose-derived mesenchymal stromal cells (DMA) was coated on the surface of the scaffold, and its biofunction was further studied. Immortalized human SZ95 sebocytes were seeded on the scaffolds so that neutral lipids were secreted for replacing meibocytes. In vitro experiments revealed excellent biocompatibility of DMA-PCL scaffolds with sebocytes. In vivo experiments revealed excellent sebocytes proliferation on the DMA–PCL scaffolds. Meanwhile, sebocytes seeded on the scaffolds secreted abundant neutral lipid in vitro and in vivo. In conclusion, a 3D-printed PCL scaffold modified with DMA was found to be a promising substitute for tarsal plate tissue engineering.

MiR-29a regulates the proliferation and differentiation of retinal progenitors by targeting Rbm8a miR-29a regulates the proliferation and differentiation of retinal progenitors by targeting Rbm8a