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Diabetes induces IL-17A-Act1-FADD-dependent retinal endothelial cell death and capillary degeneration.

ABSTRACT: PURPOSE:Diabetes leads to progressive complications such as diabetic retinopathy, which is the leading cause of blindness within the working-age population worldwide. Interleukin (IL)-17A is a cytokine that promotes and progresses diabetes. The objective of this study was to determine the role of IL-17A in retinal capillary degeneration, and to identify the mechanism that induces retinal endothelial cell death. These are clinically meaningful abnormalities that characterize early-stage non-proliferative diabetic retinopathy. METHODS:Retinal capillary degeneration was examined in vivo using the streptozotocin (STZ) diabetes murine model. Diabetic-hyperglycemia was sustained for an 8-month period in wild type (C57BL/6) and IL-17A-/- mice to elucidate the role of IL-17A in retinal capillary degeneration. Further, ex vivo studies were performed in retinal endothelial cells to identify the IL-17A-dependent mechanism that induces cell death. RESULTS:It was determined that diabetes-induced retinal capillary degeneration was significantly lower in IL-17A-/- mice. Further, retinal endothelial cell death occurred through an IL-17A/IL-17R???Act1/FADD signaling cascade, which caused caspase-mediated apoptosis. CONCLUSION:These are the first findings that establish a pathologic role for IL-17A in retinal capillary degeneration. Further, a novel IL-17A-dependent apoptotic mechanism was discovered, which identifies potential therapeutic targets for the early onset of diabetic retinopathy.

SUBMITTER: Lindstrom SI

PROVIDER: S-EPMC6690768 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Diabetes induces IL-17A-Act1-FADD-dependent retinal endothelial cell death and capillary degeneration.

Lindstrom Sarah I SI Sigurdardottir Sigrun S Zapadka Thomas E TE Tang Jie J Liu Haitao H Taylor Brooklyn E BE Smith Dawn G DG Lee Chieh A CA DeAngelis John J Kern Timothy S TS Taylor Patricia R PR

Journal of diabetes and its complications 20190529 9

<h4>Purpose</h4>Diabetes leads to progressive complications such as diabetic retinopathy, which is the leading cause of blindness within the working-age population worldwide. Interleukin (IL)-17A is a cytokine that promotes and progresses diabetes. The objective of this study was to determine the role of IL-17A in retinal capillary degeneration, and to identify the mechanism that induces retinal endothelial cell death. These are clinically meaningful abnormalities that characterize early-stage n ...[more]

PMID: 31239234

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Project description:Extensive effort has been made studying retinal pathology in Alzheimer's disease (AD) to improve early noninvasive diagnosis and treatment. Particularly relevant are vascular changes, which appear prominent in early brain pathogenesis and could predict cognitive decline. Recently, we identified platelet-derived growth factor receptor beta (PDGFRβ) deficiency and pericyte loss associated with vascular Aβ deposition in the neurosensory retina of mild cognitively impaired (MCI) and AD patients. However, the pathological mechanisms of retinal vascular changes and their possible relationships with vascular amyloidosis, pericyte loss, and blood-retinal barrier (BRB) integrity remain unknown. Here, we evaluated the retinas of transgenic APPSWE/PS1ΔE9 mouse models of AD (ADtg mice) and wild-type mice at different ages for capillary degeneration, PDGFRβ expression, vascular amyloidosis, permeability and inner BRB tight-junction molecules. Using a retinal vascular isolation technique followed by periodic acid-Schiff or immunofluorescent staining, we discovered significant retinal capillary degeneration in ADtg mice compared to age- and sex-matched wild-type mice (P < 0.0001). This small vessel degeneration reached significance in 8-month-old mice (P = 0.0035), with males more susceptible than females. Degeneration of retinal capillaries also progressively increased with age in healthy mice (P = 0.0145); however, the phenomenon was significantly worse during AD-like progression (P = 0.0001). A substantial vascular PDGFRβ deficiency (~ 50% reduction, P = 0.0017) along with prominent vascular Aβ deposition was further detected in the retina of ADtg mice, which inversely correlated with the extent of degenerated capillaries (Pearson's r = - 0.8, P = 0.0016). Importantly, tight-junction alterations such as claudin-1 downregulation and increased BRB permeability, demonstrated in vivo by retinal fluorescein imaging and ex vivo following injection of FITC-dextran (2000 kD) and Texas Red-dextran (3 kD), were found in ADtg mice. Overall, the identification of age- and Alzheimer's-dependent retinal capillary degeneration and compromised BRB integrity starting at early disease stages in ADtg mice could contribute to the development of novel targets for AD diagnosis and therapy.

Project description:BackgroundMutations of acid sphingomyelinase (ASMase) cause Niemann-Pick diseases type A and B, which are fatal inherited lipid lysosomal storage diseases, characterized with visceral organ abnormalities and neurodegeneration. However, the effects of suppressing retinal ASMase expression are not understood. The goal of this study was to determine if the disruption of ASMase expression impacts the retinal structure and function in the mouse, and begin to investigate the mechanisms underlying these abnormalities.MethodsAcid sphingomyelinase knockout (ASMase KO) mice were utilized to study the roles of this sphingolipid metabolizing enzyme in the retina. Electroretinogram and morphometric analysis were used to assess the retinal function and structure at various ages. Sphingolipid profile was determined by liquid chromatography-mass spectrometry. Western blots evaluated the level of the autophagy marker LC3-II.ResultsWhen compared to control animals, ASMase KO mice exhibited significant age-dependent reduction in ERG a- and b-wave amplitudes. Associated with these functional deficits, morphometric analysis revealed progressive thinning of retinal layers; however, the most prominent degeneration was observed in the photoreceptor and outer nuclear layer. Additional analyses of ASMase KO mice revealed early reduction in ERG c-wave amplitudes and increased lipofuscin accumulation in the retinal pigment epithelium (RPE). Sphingolipid analyses showed abnormal accumulation of sphingomyelin and sphingosine in ASMase KO retinas. Western blot analyses showed a higher level of the autophagosome marker LC3-II.ConclusionsThese studies demonstrate that ASMase is necessary for the maintenance of normal retinal structure and function. The early outer retinal dysfunction, outer segment degeneration, accumulation of lipofuscin and autophagosome markers provide evidence that disruption of lysosomal function contributes to the age-dependent retinal degeneration exhibited by ASMase KO mice.

Dataset Information

Diabetes induces IL-17A-Act1-FADD-dependent retinal endothelial cell death and capillary degeneration.

Publications

Diabetes induces IL-17A-Act1-FADD-dependent retinal endothelial cell death and capillary degeneration.

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