Retinal Inflammation Research Articles

Management of autoimmune retinopathy treated with intravitreal dexamethasone implant.

The purpose of this study is to evaluate clinical outcomes of autoimmune retinopathy (AIR) in the patients treated with intravitreal dexamethasone implant (IDI). Twenty-one eyes of 11 AIR patients treated with at least 1 injection of IDI were retrospectively reviewed. Clinical outcomes before and after treatment, including best corrected visual acuity (BCVA), optic coherence tomography (OCT), fundus autofluorescence (FAF), full-field electroretinography (ff-ERG), and visual field (VF) at last visit within 6 and/or 12months, were recorded. Among all the patients, 3 had cancer-associated retinopathy (CAR) and 8 had non-paraneoplastic-AIR (npAIR) with mean followed up of 8.52 ± 3.03months (range 4-12months). All patients achieved improved or stable BCVA within 6 and/or 12months after the treatment. Cystoid macular edema (CME) in 2 eyes and significant retinal inflammation in 4 eyes were markedly resolved after single injection. Central retinal thickness (CFT) in all eyes without CME, ellipsoid zone (EZ) on OCT in 71.4% of eyes, ERG response in 55% of eyes, and VF in 50% of eyes were stable or improved within 6months after treatment. At last visit within 12months, both BCVA and CFT remained stable in the eyes treated with either single or repeated IDI; however, progression of EZ loss and damage of ERG response occurred in some patients with single IDI. Clinical outcomes, including BCVA and parameters of OCT, ERG, and VF, were stable or improved after IDI in a majority of AIR patients. Local treatment of AIR with IDI was a good option to initiate the management or an alternative for the patients' refractory to the systemic therapy but with limited side effect.

Sustained therapeutic effect of an anti-inflammatory peptide encapsulated in nanoparticles on ocular vascular leakage in diabetic retinopathy.

Pigment epithelium-derived factor (PEDF), an endogenous Wnt signaling inhibitor in the serine proteinase inhibitors (SERPIN) super family, is present in multiple organs, including the vitreous. Significantly low levels of PEDF in the vitreous are found to associate with pathological retinal vascular leakage and inflammation in diabetic retinopathy (DR). Intravitreal delivery of PEDF represents a promising therapeutic approach for DR. However, PEDF has a short half-life after intravitreal injection, which represents a major hurdle for the long-term treatment. Here we report the prolonged therapeutic effects of a 34-mer peptide of the PEDF N-terminus, encapsulated in poly (lactic-co-glycolic acid) (PLGA) nanoparticles (PEDF34-NP), on DR. PEDF34-NP inhibited hypoxia-induced expression of vascular endothelial growth factor and reduced levels of intercellular adhesion molecule 1 (ICAM-1) in cultured retinal cells. In addition, PEDF34-NP significantly ameliorated ischemia-induced retinal neovascularization in the oxygen-induced retinopathy rat model, and significantly reduced retinal vascular leakage and inflammation in streptozotocin-induced diabetic rats up to 4weeks after intravitreal injection, as compared to PLGA-NP control. Intravitreal injection of PEDF34-NP did not display any detectable toxicities to retinal structure and function. Our findings suggest that PEDF34-NP can confer sustained therapeutic effects on retinal inflammation and vascular leakage, having considerable potential to provide long-term treatment options for DR.

Treatment with MDL 72527 Ameliorated Clinical Symptoms, Retinal Ganglion Cell Loss, Optic Nerve Inflammation, and Improved Visual Acuity in an Experimental Model of Multiple Sclerosis.

Multiple Sclerosis (MS) is a highly disabling neurological disease characterized by inflammation, neuronal damage, and demyelination. Vision impairment is one of the major clinical features of MS. Previous studies from our lab have shown that MDL 72527, a pharmacological inhibitor of spermine oxidase (SMOX), is protective against neurodegeneration and inflammation in the models of diabetic retinopathy and excitotoxicity. In the present study, utilizing the experimental autoimmune encephalomyelitis (EAE) model of MS, we determined the impact of SMOX blockade on retinal neurodegeneration and optic nerve inflammation. The increased expression of SMOX observed in EAE retinas was associated with a significant loss of retinal ganglion cells, degeneration of synaptic contacts, and reduced visual acuity. MDL 72527-treated mice exhibited markedly reduced motor deficits, improved neuronal survival, the preservation of synapses, and improved visual acuity compared to the vehicle-treated group. The EAE-induced increase in macrophage/microglia was markedly reduced by SMOX inhibition. Upregulated acrolein conjugates in the EAE retina were decreased through MDL 72527 treatment. Mechanistically, the EAE-induced ERK-STAT3 signaling was blunted by SMOX inhibition. In conclusion, our studies demonstrate the potential benefits of targeting SMOX to treat MS-mediated neuroinflammation and vision loss.

Ocular tropism of SARS-CoV-2 in animal models with retinal inflammation via neuronal invasion following intranasal inoculation

Although ocular manifestations are reported in patients with COVID-19, consensus on ocular tropism of SARS-CoV-2 is lacking. Here, we infect K18-hACE2 transgenic mice with SARS-CoV-2 using various routes. We observe ocular manifestation and retinal inflammation with production of pro-inflammatory cytokines in the eyes of intranasally (IN)-infected mice. Intratracheal (IT) infection results in dissemination of the virus from the lungs to the brain and eyes via trigeminal and optic nerves. Ocular and neuronal invasions are confirmed using intracerebral (IC) infection. Notably, the eye-dropped (ED) virus does not cause lung infection and becomes undetectable with time. Ocular and neurotropic distribution of the virus in vivo is evident in fluorescence imaging with an infectious clone of SARS-CoV-2-mCherry. The ocular tropic and neuroinvasive characteristics of SARS-CoV-2 are confirmed in wild-type Syrian hamsters. Our data can improve the understanding regarding viral transmission and clinical characteristics of SARS-CoV-2 and help in improving COVID-19 control procedures.

Spectral Domain Optical Coherence Tomography Findings in Vision-Threatening Rhino-Orbital Cerebral Mucor Mycosis-A Prospective Analysis.

Rhino-orbital cerebral mucor mycosis is a rare disease entity, where retinal involvement is described in the literature mostly as CRAO. However, pathological studies have shown mucor invading the choroid and retina with a neutrophilic reaction. So, it is pertinent that retinal inflammation secondary to invading mucor has some role in microstructural changes seen in the vitreous and retina of these patients. This novel study aims to describe the vitreal and retinal features of patients with vision-threatening rhino-orbital cerebral mucor mycosis and how they evolve on spectral domain optical coherence tomography (SD-OCT). This study shall also provide insight into the pathophysiology of these vitreoretinal manifestations by in vitro analysis of the exenterated orbital content. Fifteen eyes of fifteen patients with vision-threatening ROCM treated with standard care were enrolled in this study and underwent complete ophthalmic examination, serial colour fundus photography, and SD-OCT for both qualitative and quantitative analysis, at baseline and follow-up visits. SD-OCT on serial follow-up revealed thickening and increased inner-retinal reflectivity at presentation followed by thinning of both, other features such as the loss of the inner-retinal organized layer structure, external limiting membrane (ELM) disruption, necrotic spaces in the outer retina, and hyperreflective foci. Vitreous cells with vitreous haze were also seen. There was a significant reduction in CMT, inner and outer retinal thickness, total retinal thickness (all p < 0.05) with time, the quantum of reduction concentrated primarily to the inner retina. In summary, in vivo and in vitro analysis revealed that early microstructural changes were primarily a result of retinal infarctions secondary to thrombotic angioinvasion. With the late microstructural changes, there was possible sequelae of retinal infarction with some contribution from the inflammation, resulting from mucor invading the choroid and retina.

Exploration of the mechanisms underlying the beneficial effect of Luo Tong formula on retinal function in diabetic rats via the “gut microbiota–inflammation–retina” axis

BackgroundDiabetic retinopathy (DR) is a common microvascular complication of diabetes. Luo Tong formula (LTF), a classical traditional Chinese medicine (TCM) prescription, consists of four plants that have been widely and effectively used to treat DR. Previous work in our laboratory has confirmed that LTF can effectively ameliorate DR. However, the potential mechanism underlying the therapeutic effect of LTF on DR has not been fully elucidated. To explore the potential mechanism of action through which LTF prevents and alleviates DR from an inflammation and gut microbiota perspective.Materials and methodsMetabolite profiling of LTF was performed using liquid chromatography–mass spectrometry (LC–MS) and gas chromatography–mass spectrometry (GC–MS). Type 1 diabetes was induced in male Sprague Dawley (SD) rats via tail vein injection of 45 mg/kg streptozotocin. Next, 100 SD rats were randomly divided into four groups, normal control; diabetic control; diabetic + insulin + calcium dobesilate; and diabetic + insulin + LTF. After 12 weeks of treatment, glucose metabolism, fundus oculi, blood-retinal barrier permeability, retinal thickness, microvascular damage, as well as cell junction expression in retinas were measured and the changes observed in different groups were compared. Finally, the alteration in gut microbiota and inflammatory cytokine expression in serum and tissues were monitored, and their correlation was analyzed.ResultsA total of 1024 valid peaks were obtained for LTF using GC–MS. The HbA1c and fasting blood glucose (FBG) levels in the LTF group were slightly decreased. LTF exerted protective effects on fundus oculi and the retina structure to different degrees. LTF attenuated systemic and local retinal inflammation by significantly decreasing the levels of seven pro-inflammatory cytokines, including ICAM-1, IL-6, IL-8, MCP-1, VCAM-1, VEGF, and IL-1β. LTF restored the intestinal microbiota of diabetic rats to levels that were similar to those of normal rats. Further analysis revealed that Enterobacteriales, Prevotellaceae, Enterobacteriaceae, Bacteroides, and Klebsiella were significantly and positively correlated with the inflammatory factors in DR after LTF treatment.ConclusionsOur results revealed the mechanisms underlying the preventive effects of LTF on DR development and progression. LTF inhibited pathological changes in retinal histopathology, cell composition, and cell junction proteins while effectively ameliorating systemic and local retinal inflammation via regulating pivotal gut microbiota.

Effect and mechanism of Buyang Huanwu decoction on retinal inflammation in streptozotocin-induced diabetic rats

ObjectiveTo observe the protective effect of Buyang Huanwu decoction (BYHWD) against retinal inflammation in diabetic rats. MethodsHealthy male Wistar rats were randomly divided into normal and diabetic model groups. Diabetic rats were given a one-time intraperitoneal injection of streptozotocin (STZ) to establish a diabetic phenotype and were randomly assigned to the negative control (saline), positive control (calcium dobesilate), and BYHWD treatment groups. After 8 weeks of treatment, fluorescein-labeled dextran and Evans blue dye were injected into the tail vein to observe vascular permeability and vascular leakage in the retina, respectively. Perfusion of fluorescein-labeled concanavalin was used to detect adhesion in rat retinal leukocytes. Western blotting was used to quantify the expression levels of the inflammatory factors TNF-α, NF-κBp65, and p-NF-κBp65 in retinal tissue. ResultsCompared with nondiabetic rats, saline-treated diabetic rats showed significantly increased retinal vascular leakage, leukocyte adhesion, and protein levels of TNF-α and p-NF-κBp65 (P<0.05). These effects were significantly reduced in the positive control and BYHWD groups (P<0.05). ConclusionBuyang Huanwu decoction can ameliorate retinal inflammation in STZ-induced diabetic rats. Its mechanism of action may be related to the inhibition of TNF-α expression and NF-κB pathway activation.

The cleavage of Gasdermin E is the rate limiting step in the secretion of IL‐1β in RPE cells with non‐functional cellular clearance

AbstractPurpose: Since RPE cells has important regulatory role in retinal inflammation, we examined the secretion kinetics of proinflammatory cytokine IL‐1b.Methods: IL‐1β production and release from IL‐1a‐primed (4 ng/ml) ARPE‐19 cells was induced by inhibiting proteasomal clearance and autophagy using MG‐132 (5 μM) and Bafilomycin A1 (BafA; 50 nM), respectively. Medium samples and cell lysates were collected from the beginning of BafA exposure and continued for 24 h in 6 h intervals. IL‐1β levels were measured using the ELISA technique. The cleavage of pore forming gasdermin E was detected using the western blot method.Results: In the lysate samples, active IL‐1β levels were highest right after the BafA exposure. After 12 h, IL‐1β levels in lysates had fallen to only 54.6% of the maximal concentration. The cleavage of gasdermin E and the secretion of IL‐1β increased concurrently.Conclusions: In contrast to classical immunological cells, the secretion of IL‐1β from human RPE cells is a slow process. IL‐1β is secreted trough gasdermin E pores. Our data suggest that the secretion phase is the rate limiting step.

From biomimetic in vitro culture towards functional transplantation of hPSC‐RPE

AbstractHuman pluripotent stem cell‐derived retinal pigment epithelium (hPSC‐RPE) transplantation is currently under evaluation as treatment for macular degeneration. In our studies, we have shown that the culture substrate affects hPSC‐RPE properties in vitro, and our results also suggest that the choice of coating proteins may have implications to the functional properties of these cells also after important cryostorage cell banking. Importantly, transplanted cells must tolerate cellular stress caused by various sources such as retinal inflammation and regain their functions rapidly after the transplantation. In our studies, we have shown that the maturation level of the cultured hPSC‐RPE cells influence for example their calcium signalling properties and for the ability to tolerate cellular stress. With our collaborators, we have also studied the role of ion channels and their involvement in diverse physiological functions of hPSC‐RPEs. Last but not least, we have transplanted hPSC‐RPE as cell sheets in a novel immunosuppressed non‐human primate (NHP) model with a disrupted ocular immune privilege to study safety and submacular graft integration. In transplantations, microscope‐integrated intraoperative optical coherence tomography (miOCT)‐guided surgery, postoperative follow‐up incorporated scanning laser ophthalmoscopy, spectral domain (SD‐) OCT, and full‐field electroretinography (ERG) were used as outcome measures in addition to the histology performed after a 28‐day follow‐up. As a result, miOCT revealed foveal disruption and ERG showed amplitude and peak time preservation in cases with favourable surgical outcomes. Histology confirmed photoreceptor preservation above the grafts and in vivo phagocytosis by hPSC‐RPE, albeit evidence of cytoplasmic redistribution of opsin in photoreceptors and glia hypertrophy. The established immunosuppression protocol efficiently suppressed retinal T cell infiltration and microglia activation. As a conclusion, our results suggest the important role of biomimetic in vitro culture for the hPSC‐RPE maturation and for the functional transplantation outcome.

Watching the cell: The future of imaging in uveitis

AbstractBeing able to image individual immune cells and their live behaviour in the retina will be critical to improving our understanding and management of patients with posterior uveitis. While we can observe cells in the anterior chamber and vitreous, this often does not always reflect retinal inflammation. Many of our measures of inflammation also are indirect, such as vascular leakage, macular oedema or deterioration in the electroretinogram. I will discuss our pre‐clinical work towards this goal, efforts across the wider field and the translational pathway forward for application to uveitis patients.

The Role of Interferon Regulatory Factor 1 in Regulating Microglial Activation and Retinal Inflammation.

Microglia are resident immune cells in the central nervous system (CNS). Microglial activation plays a prominent role in neuroinflammation and CNS diseases. However, the underlying mechanisms of microglial activation are not well understood. Here, we report that the transcription factor interferon regulatory factor 1 (IRF1) plays critical roles in microglial activation and retinal inflammation by regulating pro- and anti-inflammatory gene expression. IRF1 expression was upregulated in activated retinal microglia compared to those at the steady state. IRF1 knockout (KO) in BV2 microglia cells (BV2ΔIRF1) created by CRISPR/Cas9 genome-editing technique causes decreased microglia proliferation, migration, and phagocytosis. IRF1-KO decreased pro-inflammatory M1 marker gene expression induced by lipopolysaccharides (LPS), such as IL-6, COX-2, and CCL5, but increased anti-inflammatory M2 marker gene expression by IL-4/13, such as Arg-1, CD206, and TGF-β. Compared to the wild-type cells, microglial-conditioned media (MCM) of activated BV2ΔIRF1 cell cultures reduced toxicity or death to several retinal cells, including mouse cone photoreceptor-like 661 W cells, rat retinal neuron precursor R28 cells, and human ARPE-19 cells. IRF1 knockdown by siRNA alleviated microglial activation and retinal inflammation induced by LPS in mice. Together, the findings suggest that IRF1 plays a vital role in regulating microglial activation and retinal inflammation and, therefore, may be targeted for treating inflammatory and degenerative retinal diseases.

Characterization of NLRP3 Inflammasome Activation in the Onset of Diabetic Retinopathy.

The aim of this study was to characterize the role of nucleotide-binding oligomerization domain- (NOD-) like receptor (NLR) protein 3 (NLRP3) inflammasome activation in the onset of diabetic retinopathy (DR) using retina and vitreous from donors without diabetes mellitus (CTL), with diabetes mellitus alone (DM), and with DR. Retinal expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1), the key markers of retinal inflammation, connexin43 (Cx43) which is involved in upstream inflammasome regulation, as well as NLRP3 and cleaved caspase-1, the main markers of inflammasome activation, were evaluated using immunohistochemistry and Western blotting. Vitreous interleukin (IL)-1β and IL-18, biomarkers of the activated inflammasome, were measured using a Luminex multiplex assay. Results showed a significant increase in the number and size of Iba-1+ cells and NLRP3 expression in DM, while a significant increase in GFAP, Cx43, cleaved caspase-1 and vitreous IL-18, as well as a further increase in Iba-1 and NLRP3 was found in DR. This suggests that the inflammasome is already primed in DM before its activation in DR. Furthermore, IL-18 may act as the major effector of inflammasome activation in DR while nuclear translocation of cleaved caspase-1 may play a role in gene transcription contributing to DR onset.

Pigment epithelium-derived factor is an interleukin-6 antagonist in the RPE: Insight of structure-function relationships.

Retinal and choroidal inflammatory lesions increase the levels of the pro-inflammatory cytokine interleukin-6 (IL-6). Pigment epithelium-derived factor (PEDF) has anti-inflammatory properties, but it is not known if it can prevent the production of IL-6 by the retinal pigment epithelium. To investigate the anti-inflammatory effects of PEDF in the RPE, we used human ARPE-19 cells stimulated with human recombinant tumor necrosis factor-alpha (TNF-α) to induce overexpression of the IL6 gene. We found that the viability of ARPE-19 cells decreased by 22% with TNF-α at 10ng/ml, being drastically decreased at ≥50ng/ml. TNF-α at 5-100ng/ml elevated the production and secretion of IL-6 protein, as measured by ELISA. To challenge the TNF-α-mediated stimulation of IL-6, we used recombinant human PEDF protein. PEDF at 100nM recovered the TNF-α-mediated loss of cell viability and repressed IL-6 gene expression as determined by RT-PCR. PEDF at 10-100nM attenuated the IL-6 protein secretion in a dose dependent fashion (IC50 = 65nM), being abolished with 100nM PEDF. To map the region that confers the IL-6 blocking effect to the PEDF polypeptide, we used chemically synthesized peptides designed from its biologically active domains, pro-death 34-mer, and pro-survival 44-mer and 17-mer (H105A), to challenge the IL-6 overproduction. The pro-survival peptides recovered the TNF-α-mediated cell viability loss, and inhibited IL-6 secretion, while the 34-mer did not have an effect, suggesting a role for the pro-survival domain in blocking TNF-α-mediated cell death and IL-6 stimulation. Our findings position PEDF as a novel antagonistic agent of IL-6 production in RPE cells, underscoring its use for the management of retinal disease-related inflammation.

Geraniin ameliorates streptozotocin-induced diabetic retinopathy in rats via modulating retinal inflammation and oxidative stress

BackgroundDiabetic retinopathy (DR) is the major complication of diabetes, which causes acquired vision loss in the working-age group population. ObjectiveHere, we planned to address the therapeutic roles of geraniin against the streptozotocin (STZ)-challenged DR in rats MethodologyThe DR was induced in the animals by 60 mg/kg of STZ, and then treated with 25 mg/kg of geraniin for 60 days. Later, bodyweight, food consumption, and blood glucose levels were investigated. The levels of antioxidants, MMP-9, MCP-1, and VEGF, and inflammatory cytokine status were measured using marker-specific kits. The morphometric study was conducted to assess the retinal thickness. The pancreatic tissues were analyzed microscopically. ResultsGeraniin reduced the blood glucose (270.36 ± 81 mg/dL), hemoglobin, and enhanced bodyweight (261.93 ± 72 g)in the DR rats. The antioxidant levels in the STZ-challenged DR rats were substantially improved by geraniin. Geraniin also decreased inflammatory cytokines, MCP-I, MMP-9, and VEGF levels and enhanced the retinal thickness. A histological study demonstrated that geraniin reduced the pancreatic islet cell damage in STZ-induced DR rats. ConclusionOur outcomes witnessed that geraniin reduced retinal inflammation and oxidative stress in the STZ-induced DR rats.

Unilateral asymptomatic optic disc edema: do not forget sinusitis

Background: Optic disc edema is a pathological condition with various causes. Cases of optic disc swelling should be dealt with a multidisciplinary approach to rule out those causes. Unilateral optic disc edema is seen in papillitis, non-arteritic anterior ischemic optic neuropathy, retinal vein occlusion, and infection or inflammation of the contiguous sinus or orbit. Here, we report a rare case of unilateral asymptomatic optic disc edema due to posterior ethmoid sinusitis. &#x0D; Case Presentation: A 53-year-old man presented for a routine 3-monthly follow-up after an uneventful cataract surgery of the right eye. All examinations were unremarkable, except for the right eye optic disc edema on fundus examination, consistent with an enlarged blind spot in the visual field test. Contrast-enhanced magnetic resonance imaging revealed mucosal thickening with muco-inflammatory exudates of the posterior ethmoidal sinus overriding the optic disc on the right side, leading to optic disc edema of the right eye. The patient was diagnosed with unilateral asymptomatic optic disc edema in the right eye due to posterior ethmoid sinusitis and referred to an otorhinolaryngologist for the management. The otorhinolaryngologist performed functional endoscopic sinus surgery and prescribed antibiotics and anti-histamines for 6 weeks. At the final examination, his visual acuity was 6/6, and the fundus examination revealed no optic disc edema.&#x0D; Conclusions: We reported a rare case of unilateral optic nerve edema and visual field loss with a treatable cause. Contemporary imaging provided the accurate diagnosis. Therefore, in cases of disc edema, sinusitis of the adjacent paranasal sinuses should be ruled out as a possible cause of compressive optic neuropathy or inflammation overriding the optic nerve.

Stress response protein REDD1 promotes diabetes-induced retinal inflammation by sustaining canonical NF-κB signaling

Inflammation contributes to the progression of retinal pathology caused by diabetes. Here, we investigated a role for the stress response protein regulated in development and DNA damage response 1 (REDD1) in the development of retinal inflammation. Increased REDD1 expression was observed in the retina of mice after 16-weeks of streptozotocin (STZ)-induced diabetes, and REDD1 was essential for diabetes-induced pro-inflammatory cytokine expression. In human retinal MIO-M1 Müller cell cultures, REDD1 deletion prevented increased pro-inflammatory cytokine expression in response to hyperglycemic conditions. REDD1 deletion promoted nuclear factor erythroid-2-related factor 2 (Nrf2) hyperactivation; however, Nrf2 was not required for reduced inflammatory cytokine expression in REDD1-deficient cells. Rather, REDD1 enhanced inflammatory cytokine expression by promoting activation of nuclear transcription factor κB (NF-κB). In WT cells exposed to tumor necrosis factor α (TNFα), inflammatory cytokine expression was increased in coordination with activating transcription factor 4 (ATF4)-dependent REDD1 expression and sustained activation of NF-κB. In both Müller cell cultures exposed to TNFα and in the retina of STZ-diabetic mice, REDD1 deletion promoted inhibitor of κB (IκB) expression and reduced NF-κB DNA-binding activity. We found that REDD1 acted upstream of IκB by enhancing both K63-ubiquitination and auto-phosphorylation of IκB kinase complex. In contrast with STZ-diabetic REDD1+/+ mice, IκB kinase complex autophosphorylation and macrophage infiltration were not observed in the retina of STZ-diabetic REDD1-/- mice. The findings provide new insight into how diabetes promotes retinal inflammation and support a model wherein REDD1 sustains activation of canonical NF-κB signaling.

Effect of triamcinolone acetonide on retinal inflammation and angiogenesis induced by pericyte depletion in mouse

Triamcinolone acetonide (TA) has been shown to improve morphological and functional outcome in diabetic macular edema (DME) patients. However, the functional mechanism of TA has not been elucidated yet. In this study we investigated the detailed functional mechanism of TA using culture cells and retinopathy mouse models in which retinal inflammation and abnormal angiogenesis were induced by pericyte depletion. TA significantly prevented retinal hemorrhage, edema and partially improved abnormal angiogenesis. TA decreased retinal vascular endothelial growth factor (VEGF) concentration, presumably by preventing recruitment of macrophages into retina and TA also inhibited expression of inflammatory cytokines in retina. TA inhibited proliferation/migration of vascular endothelial cells and vessel sprouting. No direct inhibition of VEGF receptor 2 (VEGFR2) autophosphorylation was observed by TA. These results suggested that TA improved inflammatory retinal events which were induced in pericyte-deleted mice by mainly decreasing macrophage-derived VEGF and expression of inflammatory cytokines followed by attenuation of vascular permeability and proliferation/migration of endothelial cells. Furthermore, in these processes, translocation of glucocorticoid receptor (GR) was partially involved.

Genetic Ablation of Nrf2 Exacerbates Neuroinflammation in Ocular Autoimmunity.

Experimental autoimmune uveoretinitis (EAU) is an animal model of non-infectious uveitis and is developed by immunization with retinal antigen, interphotoreceptor retinoid-binding protein (IRBP). Nuclear factor erythroid 2- (NF-E2-) related factor 2 (Nrf2) is responsible for regulating antioxidant and inflammatory responses. In this study, we investigated the role of Nrf2 on the development of EAU. Clinical and pathological examination demonstrated that retinal inflammation was exacerbated in Nrf2 knockout (Nrf2 KO) mice compared to wild type (WT) mice, and the expression of inflammatory cytokines (IFN-γ, IL-6, and IL-17) in the retina was significantly elevated in Nrf2 KO mice. GFAP positive cells (astrocytes) and Iba-1 positive cells (microglia cells) in the retina were more numerous in Nrf2 KO mice compared to WT mice. Furthermore, we examined the suppressive effect of the Nrf2 activator CDDO-Im (2-cyano-3,12 dioxooleana-1,9 dien-28-oyl imidazoline) on the development of EAU. The treatment with CDDO-Im significantly reduced the clinical and pathological score of EAU compared to those of vehicle-treated mice. These findings suggest that Nrf2 plays a regulatory role in the pathogenesis of autoimmune uveoretinitis and the activation of the Nrf2 system may have therapeutic potential for protecting vision from autoimmune neuroinflammation.

OCT-Based Biomarkers are Associated with Systemic Inflammation in Patients with Treatment-Naïve Diabetic Macular Edema.

Diabetic macular edema (DME) is one of the major sight-threatening complications of diabetic retinopathy, which is associated with retinal inflammation. However, it is still unknown whether DME is associated with systemic inflammation. The study aimed to investigate the association between systemic inflammatory and optical coherence tomography (OCT) biomarkers in patients with treatment-naïve center-involving diabetic macular edema (DME) and to further explore the role of systemic inflammation in DME. Medical records including clinical characteristics and ophthalmic examinations were collected from patients with treatment-naïve center-involving DME. Systemic inflammation markers including systemic immune-inflammatory index (SII), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) were calculated. OCT biomarkers, including intraretinal cyst (IRC) size, disorganization of retinal inner layers (DRIL), external limiting membrane (ELM)/ellipsoid zone (EZ) integrity, retinal hyperreflective foci (HRF), subretinal fluid (SRF) and vitreomacular (VM) status were evaluated manually. Correlation analysis and multivariable linear regression models were used to investigate the relationship between systemic inflammatory markers and OCT biomarkers. A total of 82 patients with treatment-naïve center-involving DME were included. The number of HRF on OCT was correlated with SII, NLR, and PLR and positively associated with SII (p < 0.001) in both univariate and multivariate linear regression analyses. The differences remained largely the same during subgroup analysis controlling DM duration, SRF, and ELM/EZ integrity. No significant association was observed between other OCT biomarkers and blood inflammatory markers. Retinal HRF in diabetic macular edema is associated with blood inflammatory markers, which supports the theory of HRF's inflammatory nature and emphasizes the important role of inflammation in DME. SII may be a potential marker for DME treatment decisions.

Nicotinamide Mononucleotide Prevents Retinal Dysfunction in a Mouse Model of Retinal Ischemia/Reperfusion Injury.

Retinal ischemia/reperfusion (I/R) injury can cause severe vision impairment. Retinal I/R injury is associated with pathological increases in reactive oxygen species and inflammation, resulting in retinal neuronal cell death. To date, effective therapies have not been developed. Nicotinamide mononucleotide (NMN), a key nicotinamide adenine dinucleotide (NAD+) intermediate, has been shown to exert neuroprotection for retinal diseases. However, it remains unclear whether NMN can prevent retinal I/R injury. Thus, we aimed to determine whether NMN therapy is useful for retinal I/R injury-induced retinal degeneration. One day after NMN intraperitoneal (IP) injection, adult mice were subjected to retinal I/R injury. Then, the mice were injected with NMN once every day for three days. Electroretinography and immunohistochemistry were used to measure retinal functional alterations and retinal inflammation, respectively. The protective effect of NMN administration was further examined using a retinal cell line, 661W, under CoCl2-induced oxidative stress conditions. NMN IP injection significantly suppressed retinal functional damage, as well as inflammation. NMN treatment showed protective effects against oxidative stress-induced cell death. The antioxidant pathway (Nrf2 and Hmox-1) was activated by NMN treatment. In conclusion, NMN could be a promising preventive neuroprotective drug for ischemic retinopathy.