Fibrosis, a common end point of chronic inflammatory diseases across organs, remains a major therapeutic challenge. Macrophages are central regulators of fibrotic remodeling, with evidence suggesting their direct role through macrophage-to-myofibroblast transition. However, the upstream mechanisms governing macrophage fibrogenic reprogramming remain unclear. Using a laser-induced mouse model of subretinal fibrosis, whether adhesion-dependent mechanotransduction regulates macrophage-driven fibrosis was investigated. Bulk RNA sequencing of retinal pigment epithelium-choroid tissues revealed significant enrichment of adhesion-related genes and focal adhesion pathways, with up-regulation of integrins such as Itgb2, Itgal, and Itgax. Increased integrin expression and focal adhesion kinase (FAK) phosphorylation were detected in infiltrating F4/80+ macrophages within fibrotic lesions. Bone marrow-derived macrophages under high adherence conditions expressed higher levels of fibrosis-related genes and FAK-related genes such as Ptk2 and Ptk2b. FAK inhibitor PF562271 suppressed transforming growth factor-β1-induced up-regulation of fibrosis-related genes (Col1a1, Fn1, and Acta2) and α-smooth muscle actin in macrophages. I.P. administration of PF562271 reduced expression of adhesion molecules ITGB2 and ITGAL on circulating monocytes and alleviated subretinal fibrosis. These findings identify integrin-FAK-mediated mechanotransduction as a key regulator of macrophage fibrogenic reprogramming and macrophage-to-myofibroblast transition. Adhesion-dependent signaling is highlighted as a conserved pathway linking tissue remodeling to fibrotic macrophage activation and FAK as a potential therapeutic target.

Abstract Inflammatory arthritis and uveitis frequently co-exist, yet the mechanisms linking joint and ocular inflammation remain ill-defined. Here, we investigated how inflammatory arthritis influences ocular immune homeostasis using murine models of antigen-induced arthritis and collagen-induced arthritis. Arthritis promoted the accumulation of T cells, myeloid cells, and neutrophils within the vitreoretinal compartment, without progression to overt clinical uveitis. Ocular leukocyte recruitment was dynamically coupled to arthritis activity, resolving with remission of joint inflammation and recurring during arthritic flares. The magnitude of ocular immune perturbation correlated with arthritis severity, being enhanced in IL-27R-deficient mice and markedly reduced in IL-6R-deficient mice. Mechanistically, arthritis increased blood-retinal barrier permeability, demonstrating that systemic inflammation perturbs ocular immune privilege even in the absence of apparent ocular disease. While arthritis alone was insufficient to induce uveitis, it established a permissive ocular microenvironment that selectively enhanced the recruitment of adoptively transferred uveitogenic CD4 + T cells. These findings identify inflammatory arthritis as a systemic driver of subclinical ocular immune dysregulation and reveal a mechanism by which inflammation at a distant site may promote vulnerability to ocular autoimmunity. These data provide a framework for understanding immune dysregulation at the joint-eye axis and highlight cytokine pathways that may be targeted to preserve ocular immune homeostasis.

Pathologic myopia is a major cause of irreversible visual impairment worldwide and is characterized by excessive axial elongation accompanied by progressive retinal degeneration. Whether vision loss results primarily from passive retinal stretching or selective neurodegeneration remains unclear, hindering the development of effective neuroprotective and regenerative therapies. Here, we investigated retinal neuronal, vascular, and glial alterations in retinal pigment epithelium (RPE)-specific Lrp2 knockout (Best1-Cre/Lrp2fl/fl conditional knockout, CKO) model of pathologic myopia. The CKO mice were examined longitudinally using multimodal ocular imaging, electroretinography, optokinetic testing, fluorescein angiography, and quantitative immunohistochemistry analysis. CKO phenotype+ mice developed early-onset, progressive axial elongation and high myopia, accompanied by fundus features closely resembling human pathologic myopia, including peripapillary and patchy chorioretinal atrophy. Retinal function was markedly impaired, with significant reductions in scotopic a-, b-, and c-wave amplitudes. Although axial elongation resulted in a 1.98-fold increase in retinal surface area and a 55.95% reduction in retinal thickness, quantitative correction for retinal expansion revealed selective neuronal loss rather than uniform retinal degeneration. Total numbers of rods, cones, horizontal cells, and GABAergic amacrine cells were reduced by 22, 40, 30, and 57%, respectively, together with a 66% loss of photoreceptor synaptic ribbons. In contrast, retinal ganglion cells and bipolar cells exhibited reduced density but preserved absolute cell numbers. These neuronal changes were accompanied by retinal and choroidal microvascular degeneration, Müller gliosis, microglial activation and subretinal accumulation, and RPE dysmorphology. Our findings demonstrate that axial elongation induces neuron subtype–specific degeneration rather than generalized retinal thinning. Our study identifies photoreceptors, horizontal cells, and inhibitory amacrine cells as particularly vulnerable populations and implicates impaired RPE support, neurovascular dysfunction, and chronic glial activation as key mechanisms driving myopic retinopathy. This study provides a mechanistic framework for developing targeted neuroprotective and regeneration-based therapies for pathologic myopia.

Abstract Background Subretinal fibrosis causes irreversible vision loss in neovascular age-related macular degeneration (nAMD). Sustained macular inflammation drives the initiation and progression of fibrosis by activating profibrotic cells and perpetuating tissue damage. This study investigated the therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in mitigating nAMD-associated subretinal fibrosis. Methods MSC-EVs were prepared from human bone marrow-derived MSCs and characterized using nanoparticle tracking analysis, transmission electron microscopy, and Western Blotting. Subretinal fibrosis was induced in C57BL/6J mice using the two-stage laser-induced model. MSC-EVs were injected either intravitreally (1 × 10 8 particles/eye, single injection) or retro-orbitally (1 × 10 8 particles, two injections four days apart) immediately after the second laser. Eyes were collected 10 days post-second laser for immunostaining of collagen-1 and CD31 or iso-lectin B4. In vitro, primary human RPE and ARPE-19 cells were treated with TGF-β2 (10 ng/mL) to induce epithelial-mesenchymal transition (EMT); peritoneal macrophages were treated with TGF-β1 (10 ng/mL) to induce macrophage-to-myofibroblast transition (MMT). After 48 h, cells were treated with MSC-EVs (cell-to-MSC-EV ratio = 1:2000) for 3 days. Myofibroblast markers (αSMA, fibronectin, and collagen-1) were examined by immunocytochemistry and quantitative PCR (qPCR). Human iPCS-derived macrophages (iMACs), bone-marrow-derived macrophages, peritoneal macrophages, and BV2 microglia were treated with LPS (100 ng/mL) and IFN-γ (20 ng/mL) for 24 h with or without MSC-EVs (1:2000). Small RNA sequencing was used to identify specific functional molecules within MSC-EVs. Immune-related gene expressions were evaluated by qPCR. Results Intravitreal and retroorbital administration of MSC-EVs reduced collagen-1 + fibrotic lesions by 46% and 30%, respectively, and significantly inhibited infiltrating Iba-1 + cells. In vitro, MSC-EVs attenuated TGF-β2-induced upregulation of αSMA, fibronectin, and collagen-1 at both protein and mRNA levels in RPE cells. Similarly, the expression of Acta2 , Fn1 , and Col1a1 in TGF-β1-treated macrophages was also significantly reduced following MSC-EV treatment. In LPS + IFN-γ-stimulated immune cells, MSC-EVs significantly suppressed the expression of Il6 and Il1b in all cell types, and reduced the expression of Inos , Tnfa , and Cd86 in iMACs, peritoneal macrophages, and BV2 cells. Enriched hsa-miR-21-5p was identified in MSC-EVs and involved in the TGF-β-related signaling pathway. Overexpression of miR-21-5p mimic abrogated the TGF-β1-driven upregulation of pro-fibrotic markers in RPE and macrophages. Conclusions Local administration of MSC-EVs effectively mitigated subretinal fibrosis and reduced inflammation in the mouse model of nAMD, potentially via miR-21-5p-mediated attenuation of EMT and MMT, and suppression of inflammation. MSC-EVs represent a novel cell-free therapeutic strategy for macular fibrosis in nAMD.

BackgroundAirborne pollutants comprise biological agents such as lipopolysaccharide (LPS) and engineered nanomaterials, including carbon nanotubes (CNTs), which are increasingly prevalent in industrial and consumer applications. Although the pulmonary toxicity of high-dose CNT exposure is established, the inflammatory consequences of low-dose, non-cytotoxic CNT exposure, particularly in combination with other aerosols, remain poorly understood.MethodsWe investigated cytotoxicity and proinflammatory responses to multi-walled CNTs in three-dimensional A549 human epithelial spheroids, compared with A549 monolayers and MM6 monocytes. Cells were exposed to two CNTs differing in diameter (CNT1: 7–15 nm; CNT2: 110–170 nm), alone or combined with LPS. Cell viability was assessed by WST-1 assay and F-actin junction staining, while IL-8 and IL-6 production was quantified by ELISA and qPCR.ResultsA549 spheroids were more susceptible to CNT-induced cytotoxicity than monolayers, with CNT1 inducing greater cytotoxicity than CNT2. At non-cytotoxic concentrations, CNTs alone did not elicit cytokine release; however, co-exposure with LPS significantly enhanced cytokine secretion in spheroids, particularly in the presence of CNT2. This synergistic inflammatory response was not observed in MM6 monocytes.ConclusionOur study demonstrates that non-cytotoxic CNTs can potentiate LPS-driven inflammation in A549 epithelial spheroids, suggesting potential respiratory risks from combined exposure to environmental endotoxins and nanomaterials, even at low doses.

To investigate the stage-specific role of NK1.1⁺ cells in two experimental models of retinal injury: laser-induced choroidal neovascularization (CNV) and retinal detachment (RD). The study used C57BL/6J mice (8–12 weeks). NK1.1+ cells were depleted either during the acute phase (< 48 h after injury) or throughout the disease progression (i.e., 2, 4, and 6 days after laser injury) using anti-NK1.1 antibody (PK136). The outcome measurements included CNV lesion size in RPE/choroid/sclera flatmounts (following collagen IV staining), photoreceptor death (with TUNEL staining), RPE/choroidal infiltrating myeloid cells (by Iba-1 immunostaining), and innate lymphocytes (e.g., assessed in blood, spleen, and ocular single-cell suspension by flow cytometry and immunofluorescence on RPE/choroid/sclera for CD45NK1.1⁺ (including NK and ILC1), CD45+CD3⁻T-bet⁺ (ILC1), CD45+CD127+GATA3+ (ILC2), and CD45+CD127+RORγ+ (ILC3)). Retinal laser injury increased circulating NK, ILC1, and ILC2 cells at 1 h (p < 0.05), accompanied by the accumulation of infiltrating ILC1/2 cells (p < 0.001). The number of infiltrating NK1.1+ cells increased progressively from 1 to 24 h (CNV, p < 0.001; RD, p < 0.01). Sustained NK1.1+ cell depletion significantly reduced circulating NK and ILC1 cells, exacerbated collagen IV+ CNV (p < 0.05) and increased the number of infiltrating Iba-1+ cells (p < 0.001). In contrast, NK1.1⁺ cell (NK and ILC1) depletion either immediately after or 48 h before injury significantly reduced the severity of laser-induced CNV (p < 0.05) and suppressed Iba-1+ cell infiltration (p < 0.05). Early NK1.1+ cell (NK and ILC1) depletion also attenuated RD-mediated TUNEL+ apoptotic photoreceptors (p < 0.01) and reduced infiltrating Iba-1+ cells (p < 0.05). NK1.1⁺ cells exert stage-dependent effects in retinal injury, amplifying inflammation during the acute phase while contributing to immune regulation at later stages.

Purpose:The purpose of this study was to understand how the gut microbial system responds to retinal injury. Methods:Adult C57BL/6J mice were subjected to retinal laser burns or hypotony-induced retinal detachment (RD). One, 4, and 24 hours later, gut permeability (8 male mice and 8 female mice) was assessed using Evan's blue assay and the expression of ZO-1 in intestinal epithelial cells was examined by immunofluorescence. Circulating immune cells were evaluated by flow cytometry. The feces from control and lasered mice (n = 8) were collected under strict sterile conditions and processed for 16S DNA paired-end sequencing using the Illumina platform. The impact of gut dysbiosis on retinal wound healing was evaluated following treatment with Peros antibiotics (n = 8). Retinal pathologies were examined by immunohistochemistry. Results:Retinal laser injury significantly altered gut microbial profiles within 1 hour (β-diversity, multi-response permutation procedure [MRPP], P = 0.05). The abundance of Lignipirellula and Faecalibacterium was 100- and 6.67-fold lower, and the abundance of Akkermansia and Colidextribacter was 3.65- and 17.72-fold higher than non-lasered controls, respectively. Retinal laser burns and RD, not sham surgery, increased gut permeability at 1 hour and 4 hours by 3.82- and 24.76-fold, respectively, disrupted intestinal epithelial ZO-1 expression, accompanied by an increased population of circulating neutrophils and monocytes (P < 0.01) at 1 hour and 4 hours. Antibiotic treatment attenuated laser-/RD-induced gut permeability and the increased neutrophils and monocytes (in RD, P < 0.05). Antibiotic treatment also significantly reduced the severity of laser-induced choroidal neovascularization (CNV; P < 0.001) and RD-mediated photoreceptor apoptosis (P < 0.01), and suppressed Gr-1+ neutrophils (CNV, P < 0.001) and Iba-1+ cell infiltration (P < 0.001). Conclusions:A retina-gut axis exists. Retinal injury induces rapid gut microbial alteration, which in turn modulates innate immune cell activation and regulates the wound healing response.

PurposeTo investigate the impact of low-dose, long-term aspirin use on neovascular age-related macular degeneration (nAMD).MethodsAdult C57BL/6J or Thbs-1–/– mice were treated with daily aspirin (1.25 mg/kg) for 8 weeks before being subjected to laser-induced choroidal neovascularization (CNV). The animals were left for 7–10 days with continued aspirin use before the eyes were collected for further investigations. Bone marrow-derived macrophages (BMDMs) and primary retinal pigment epithelial (RPE) cells were treated with different concentrations of aspirin (1, 10, 100 μM) for two days before being subjected to LPS+IFNγ for 16 h. The expression of cytokine genes was evaluated by qRT-PCR. The concentrations of thrombospondin-1 (TSP-1) were measured by ELISA.ResultsAspirin treatment did not affect circulating immune cell profiles in normal mice but significantly increased CD11b+ cells in laser-induced CNV mice. The treatment significantly increased the severity of laser-induced CNV and reduced serum levels of TSP-1. In vitro aspirin treatment upregulated Tnfa and Ccl22, down-regulated Thbs-1 mRNA expression, and reduced TSP-1 production in LPS+IFNγ-treated M1 BMDMs but not RPE cells. Thbs-1–/– mice developed severe laser-induced CNV, which was not affected by aspirin intervention. nAMD patients had significantly lower serum levels of TSP-1 than healthy controls, although no significant difference was found between nAMD patients with and without aspirin use.ConclusionLow-dose long-term aspirin use promoted the severity of laser-induced CNV by down-regulating TSP-1. Lower serum levels of TSP-1 may be a risk factor for nAMD. The long-term ocular safety of aspirin should be validated in prospective cohorts.

Age is a primary risk factor for chronic conditions, including age-related macular degeneration (AMD). Impairments in autophagy processes are implicated in AMD progression, but the extent of autophagy's contribution and its therapeutic potential remain ambiguous. This study investigated age-associated transcriptomic changes in autophagy pathways in the retinal pigment epithelium (RPE) and evaluated the protective effects of topical trehalose, an autophagy-enhancing small molecule, against light-induced outer retinal degeneration in mice. Transcriptomic analysis of human RPE/choroid and mouse RPE revealed consistent downregulation of autophagy pathways with age, alongside variable changes as AMD severity progressed. Given the age- and AMD-associated perturbation of autophagy pathways, we examined trehalose treatment in vitro, which enhanced autophagic flux and restored mitochondrial respiratory function in primary murine RPE cells exposed to oxidative stress. In vivo, topical trehalose improved autophagy-lysosome activity in mouse RPE, as demonstrated by elevated LC3B turnover and SQSTM1/p62 degradation. Furthermore, trehalose eyedrops protected mice from light-induced damage to the RPE and photoreceptors, preserving outer nuclear layer thickness, RPE morphology, and junctional F-actin organization. Taken together, the data support that age-related decline and severe dysregulation in autophagy contributed to AMD progression. By restoring autophagic flux, topical trehalose demonstrates therapeutic potential to address early autophagy-related pathological changes in AMD.

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.

PurposeTo investigate the microbial profiles in the retina and RPE/choroid, and how they respond to retinal injury.MethodsAdult C57BL/6J mice were subjected to retinal laser burns using a photocoagulator. One and 24h later, the retina and RPE/choroid were collected under strict sterile conditions and processed for 16S rRNA paired-end sequencing (2×250). The data were analyzed using R software, GraphPad Prism, OmicShare, and Wekemo Bioincloud.ResultsMicrobiota were detected in the retina and RPE/choroid under normal physiological conditions. The alpha diversity was higher in the retina than in the RPE/choroid. All retinal microbiotas at the phylum level and 12 out of 14 at the genus level were shared with those of RPE/choroid. The top phyla were Firmicutes, Proteobacteria, and Actinobacteria. Retinal laser injury reduced the alpha diversity but did not affect beta diversity. In the RPE/choroid, the abundance of Actinomyces and Roseburia decreased, and the abundance of Lactobacillus increased significantly after laser injury. The abundance of Sphingomonas in the retina decreased, and the abundance of Faecalibacterium and Bifidobacterium increased (P<0.05) after laser injury in the retina. Faecalibacterium and Bifidobacterium are positively linked to Th17/IL-17 signaling and RIG-I-like receptor signaling pathways, as well as antigen processing and presentation.ConclusionsThe neuroretina and RPE/choroid have diverse microbiomes under normal conditions. Their richness and evenness are relatively stable in the retina compared to those in the RPE/choroid. Retinal laser injury enriches Faecalibacterium and Bifidobacterium in ocular tissues, and these microbiotas may participate in retinal wound healing through modulating inflammation.

Chronic inflammation is a constitutive component of many age-related diseases, including age-related macular degeneration (AMD). Here, we identified interleukin-1 receptor–associated kinase M (IRAK-M) as a key immunoregulator in retinal pigment epithelium (RPE) that declines during the aging process. Rare genetic variants of IRAK3 , which encodes IRAK-M, were associated with an increased likelihood of developing AMD. In human samples and mouse models, IRAK-M abundance in the RPE declined with advancing age or exposure to oxidative stress and was further reduced in AMD. Irak3 -knockout mice exhibited an increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M led to a disruption in RPE cell homeostasis, characterized by compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of adeno-associated virus (AAV)–expressing human IRAK3 rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in Irak3 -knockout mice. Our data show that replenishment of IRAK-M in the RPE may redress dysregulated pro-inflammatory processes in AMD, suggesting a potential treatment for retinal degeneration.

Inflammation plays a key role in the progression of choroidal neovascularization (CNV). Regular intravitreal injection of anti-VEGF medication is required for many patients to sustain eye condition as CNV always recurs due to persistent chronic inflammation in the retina and choroid. Marine bromophenols (BDB) have been widely studied due to their diverse bioactivities, including anti-inflammatory effect, though the mechanism of which remained unclear. Our study demonstrated that BDB could restricted endothelial cells' function and suppressed choroidal explants both in vitro and in vivo without out affecting the cells viability. BDB also significantly reduced numerous inflammatory cytokines in both raw cells and choroidal tissue, including IL-1β, IL-6, TNF-α, IL-4 and MMP-9. Moreover, we demonstrated that BDB down regulated phosphorylation of NF-κB p65 in the raw cells. By Co-IP assay, HUWE1 was found to be bound with BDB and the binding location was at sequences position 4214. When overexpressed HUWE1 in HUVECs, the suppression of endothelial cells' function by BDB became more significant. Taken together, the findings in this study showed that BDB suppressed endothelial cells' function and choroidal neovascularization by targeting HUWE1 through NF-κB pathway, which suggested that BDB could be a potential therapeutic candidate in treating chronic inflammation in choroidal neovascularization.

Abstract Background Retinal fibrosis affects 40–70% of neovascular age-related macular degeneration patients. This study investigated the effect of ageing on subretinal fibrosis secondary to choroidal neovascularization and the mechanism of action. Methods Subretinal fibrosis was induced in young (2.5-month) and aged (15–16-month) C57BL/6J mice using the two-stage laser protocol. Five and 30 days later, eyes were collected and stained for CD45 and collagen-1 and observed by confocal microscopy. Fibrocytes (CD45+collagen-1+) were detected in the bone marrow (BM), blood and fibrotic lesions by flow cytometry and confocal microscopy, respectively. BM-derived macrophages (BMDMs) were cultured from young and aged mice with or without TGF-β1 (10 ng/mL) treatment. The expression of mesenchymal marker αSMA (Acta2), fibronectin (Fn1) and collagen-1 (Col1a1) was examined by qPCR and immunocytochemistry, whereas cytokine/chemokine production was measured using the Luminex multiplex cytokine assay. BM were transplanted from 22-month (Ly5.2) aged mice into 2.5-month (Ly5.1) young mice and vice versa. Six weeks later, subretinal fibrosis was induced in recipient mice and eyes were collected for evaluation of fibrotic lesion size. Results Under normal conditions, the number of circulating fibrocytes (CD45+collagen-1+) and the expression levels of Tgfb1, Col1a1, Acta2 and Fn1 in BMDMs were significantly higher in aged mice compared to young mice. Induction of subretinal fibrosis significantly increased the number of circulating fibrocytes, enhanced the expression of Col1a1, Acta2 and Fn1 and the production of soluble urokinase plasminogen activator surface receptor (suPAR) but decreased the production of CXCL10 in BMDMs. BMDMs from aged subretinal fibrosis mice produced significantly higher levels of VEGF, angiopoietin-2 and osteopontin than cells from young subretinal fibrosis mice. The subretinal fibrotic lesion in 15–16-month aged mice was 62% larger than that in 2.5-month young mice. The lesion in aged mice contained a significantly higher number of fibrocytes compared to that in young mice. The number of circulating fibrocytes positively correlated with the size of subretinal fibrotic lesion. Transplantation of BM from aged mice significantly increased subretinal fibrosis in young mice. Conclusions A retina–BM–blood–retina pathway of fibrocyte/macrophage recruitment exists during retinal injury. Ageing promotes subretinal fibrosis through higher numbers of circulating fibrocytes and profibrotic potential of BM-derived macrophages.

Somatostatin, a naturally produced neuroprotective peptide, depresses excitatory neurotransmission and exerts anti-proliferative and anti-inflammatory effects on the retina. In this review, we summarize the progress of somatostatin treatment of diabetic retinopathy through analysis of relevant studies published from February 2019 to February 2023 extracted from the PubMed and Google Scholar databases. Insufficient neuroprotection, which occurs as a consequence of declined expression or dysregulation of retinal somatostatin in the very early stages of diabetic retinopathy, triggers retinal neurovascular unit impairment and microvascular damage. Somatostatin replacement is a promising treatment for retinal neurodegeneration in diabetic retinopathy. Numerous pre-clinical and clinical trials of somatostatin analog treatment for early diabetic retinopathy have been initiated. In one such trial (EUROCONDOR), topical administration of somatostatin was found to exert neuroprotective effects in patients with pre-existing retinal neurodysfunction, but had no impact on the onset of diabetic retinopathy. Overall, we concluded that somatostatin restoration may be especially beneficial for the growing population of patients with early-stage retinopathy. In order to achieve early prevention of diabetic retinopathy initiation, and thereby salvage visual function before the appearance of moderate non-proliferative diabetic retinopathy, several issues need to be addressed. These include the needs to: a) update and standardize the retinal screening scheme to incorporate the detection of early neurodegeneration, b) identify patient subgroups who would benefit from somatostatin analog supplementation, c) elucidate the interactions of somatostatin, particularly exogenously-delivered somatostatin analogs, with other retinal peptides in the context of hyperglycemia, and d) design safe, feasible, low cost, and effective administration routes.