Resolution of Inflammation in Retinal Disorders: Briefly the State

Trotta, Maria Consiglia; Gesualdo, Carlo; Petrillo, Francesco; Lepre, Caterina Claudia; Corte, Alberto Della; Cavasso, Giancuomo; Maggiore, Giulia; Simonelli, Francesca; D’Amico, Michele; Rossi, Silvia

doi:10.3390/ijms23094501

Cited by 13 publications

(9 citation statements)

References 69 publications

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“…In the context of DR, hyperreflective retinal spots (HRS) are clinically observed by physicians using optical coherence tomography. Studies have reported a positive correlation between IBA1-positive MG activation and retinal HRS in patients with non-PDR (NPDR) and PDR [53]. Our results revealed that in the diabetic coculture conditions, G10 and G25, a considerably higher IBA1…”

Section: Impact Of Glucose Levels On Ec and Mg Phenotypessupporting

confidence: 53%

3D bioprinted endothelial cell-microglia coculture for diabetic retinopathy modeling

Wu,

Xu,

Luo

et al. 2023

Biofabrication

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Diabetic retinopathy (DR) is a common diabetes complication leading to vision impairment or blindness due to retinal vasculature alterations. Hyperglycemia induces structural alterations, inflammation, and angiogenic factor upregulation. Current treatments targeting vascular endothelial growth factor (VEGF) are insufficient for approximately 20% of DR patients, necessitating alternative approaches. Microglia, essential for retinal homeostasis, remains underexplored in DR. This study used digital light processing bioprinting to construct a 3D coculture model of endothelial cells (ECs) and microglia under varying glucose conditions, with a hydrogel stiffness of 4.6-7.1 kPa to mimic the extracellular matrix property of retina plexiform. Our results showed that high glucose levels influenced both EC and microglial phenotypes, gene expression, and angiogenic potential. Increasing glucose from 5 mM to 25 mM reduces drug efficacy by 17% for Aflibercept in EC monoculture, and 25% and 30% for Aflibercept and Conbercept in EC-microglia coculture, respectively, suggesting that diabetic condition and microglia presence could interfere with drug responses. In conclusion, our findings emphasize the importance of cellular interactions and microenvironmental factors in DR therapy, aiming to identify novel strategies and improve understanding of microglia's role in disease pathogenesis.

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Section: Impact Of Glucose Levels On Ec and Mg Phenotypessupporting

confidence: 53%

3D bioprinted endothelial cell-microglia coculture for diabetic retinopathy modeling

Wu,

Xu,

Luo

et al. 2023

Biofabrication

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“…It has been described that the increase in the IL-4 release by glial cells may be a mechanism to suppress the exaggerated pro-inflammatory response [ 68 , 69 ], namely the elevated levels of IL-6 and TNF [ 70 ], which seems to be in accordance with our results. Moreover, a pro-inflammatory environment plays an important role in retinal dysfunction [ 71 ], which is in accordance with the alterations in retinal function detected in the untreated ADHD animal model. Moreover, treatment with MPH decreased TNF and iNOS levels and showed a tendency for the same effect concerning IL-6.…”

Section: Discussionmentioning

confidence: 57%

Attention-Deficit/Hyperactivity Disorder Animal Model Presents Retinal Alterations and Methylphenidate Has a Differential Effect in ADHD versus Control Conditions

et al. 2023

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Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most prevalent neurodevelopmental disorders. Interestingly, children with ADHD seem to experience more ophthalmologic abnormalities, and the impact of methylphenidate (MPH) use on retinal physiology remains unclear. Thus, we aimed to unravel the retina’s structural, functional, and cellular alterations and the impact of MPH in ADHD versus the control conditions. For that, spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were used as animal models of ADHD and the controls, respectively. Animals were divided into four experimental groups as follows: WKY vehicle (Veh; tap water), WKY MPH (1.5 mg/kg/day), SHR Veh, SHR MPH. Individual administration was performed by gavage between P28-P55. Retinal physiology and structure were evaluated at P56 followed by tissue collection and analysis. The ADHD animal model presents the retinal structural, functional, and neuronal deficits, as well as the microglial reactivity, astrogliosis, blood-retinal barrier (BRB) hyperpermeability and a pro-inflammatory status. In this model, MPH had a beneficial effect on reducing microgliosis, BRB dysfunction, and inflammatory response, but did not correct the neuronal and functional alterations in the retina. Curiously, in the control animals, MPH showed an opposite effect since it impaired the retinal function, neuronal cells, and BRB integrity, and also promoted both microglia reactivity and upregulation of pro-inflammatory mediators. This study unveils the retinal alterations in ADHD and the opposite effects induced by MPH in the retina of ADHD and the control animal models.

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“…Another potentially useful class of such molecules is the lipidic pro-resolving mediators called lipoxins, specifically lipoxin-A4 (LXA4). LXA4 is synthesized in the inner retina and its levels decrease following eye injury ( 73 ). Both NPDR and PDR patients have lower serum levels of LXA4 compared to diabetics without retinopathy; lipoxin-A4 levels were also lower in the vitreous of PDR patients ( 74 ).…”

Section: Role Of Nets In the Complications Of Diabetesmentioning

confidence: 99%

Emerging role of neutrophil extracellular traps in the complications of diabetes mellitus

et al. 2022

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Immune dysfunction is widely regarded as one of the central tenants underpinning the pathophysiology of diabetes mellitus (DM) and its complications. When discussing immunity, the role of neutrophils must be accounted for: neutrophils are the most abundant of the circulating immune cells and are the first to be recruited to sites of inflammation, where they contribute to host defense via phagocytosis, degranulation, and extrusion of neutrophil extracellular traps (NETs). NETs are composed of DNA associated with nuclear and cytosolic neutrophil proteins. Although originally reported as an antimicrobial strategy to prevent microbial dissemination, a growing body of evidence has implicated NETs in the pathophysiology of various autoimmune and metabolic disorders. In these disorders, NETs propagate a pathologic inflammatory response with consequent tissue injury and thrombosis. Many diabetic complications—such as stroke, retinopathy, impaired wound healing, and coronary artery disease—involve these mechanisms. Therefore, in this review, we discuss laboratory and clinical data informing our understanding of the role of NETs in the development of these complications. NET markers, including myeloperoxidase, citrullinated histone H3, neutrophil elastase, and cell-free double-stranded DNA, can easily be measured in serum or be detected via immunohistochemical/immunocytochemical staining of tissue specimens. Therefore, NET constituents potentially constitute reliable biomarkers for use in the management of diabetic patients. However, no NET-targeting drug is currently approved for the treatment of diabetic complications; a candidate drug will require the outcomes of well-designed, robust clinical trials assessing whether NET inhibition can benefit patients in terms of morbidity, quality of life, health expenditures, and mortality. Therefore, much work remains to be done in translating these encouraging pieces of data into clinical trials for NET-targeting medications to be used in the clinic.

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Resolution of Inflammation in Retinal Disorders: Briefly the State

Cited by 13 publications

References 69 publications

3D bioprinted endothelial cell-microglia coculture for diabetic retinopathy modeling

3D bioprinted endothelial cell-microglia coculture for diabetic retinopathy modeling

Attention-Deficit/Hyperactivity Disorder Animal Model Presents Retinal Alterations and Methylphenidate Has a Differential Effect in ADHD versus Control Conditions

Emerging role of neutrophil extracellular traps in the complications of diabetes mellitus

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