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Photoreceptor cells produce inflammatory products that contribute to retinal vascular permeability in a mouse model of diabetes.

ABSTRACT: AIMS/HYPOTHESIS:Recent studies suggest that photoreceptor cells produce mediators or products that contribute to retinal capillary damage in diabetes. The purpose of this study was to determine if photoreceptor cells release soluble factors that contribute to retinal vascular permeability in diabetes. METHODS:To assess retinal vascular leakage, a streptozotocin-induced mouse model of diabetes, with hyperglycaemia for 8 months, and age-matched control mice, were injected with FITC-BSA. Fluorescence microscopy was used to detect leakage of FITC-BSA from the retinal vasculature into the neural retina. Ex vivo and in vitro experiments were performed to determine if photoreceptor cells released products that directly increased retinal endothelial cell permeability or cell death. Effects of products released by photoreceptors on tight junction and cell adhesion proteins were assessed by quantitative reverse transcription PCR (qRT-PCR). Inflammatory products released by photoreceptors into media were measured using protein arrays. RESULTS:Eight months duration of diabetes increased retinal vascular permeability in wild-type mice, but this defect was inhibited in opsin-deficient diabetic mice in which photoreceptor cells had degenerated earlier. Photoreceptor cells from diabetic wild-type mice released inflammatory products (e.g. IL-1?, IL-1?, IL-6, IL-12, chemokine C-X-C motif ligand 1 [CXCL1], monocyte chemoattractant protein 1 [MCP-1], CXCL12a, I-309, chemokine ligand 25 [CCL25] and TNF-?), which directly contributed to increased retinal endothelial cell permeability, at least in part via changes in claudin (tight junction) mRNA. Products released from photoreceptor cells from diabetic mice or under diabetes-like conditions did not directly kill retinal endothelial cells in vitro. CONCLUSIONS/INTERPRETATION:Photoreceptor cells can produce inflammatory products that contribute to retinal vascular permeability in mouse models of diabetes.

SUBMITTER: Tonade D

PROVIDER: S-EPMC5660634 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Photoreceptor cells produce inflammatory products that contribute to retinal vascular permeability in a mouse model of diabetes.

Tonade Deoye D Liu Haitao H Palczewski Krzysztof K Kern Timothy S TS

Diabetologia 20170728 10

<h4>Aims/hypothesis</h4>Recent studies suggest that photoreceptor cells produce mediators or products that contribute to retinal capillary damage in diabetes. The purpose of this study was to determine if photoreceptor cells release soluble factors that contribute to retinal vascular permeability in diabetes.<h4>Methods</h4>To assess retinal vascular leakage, a streptozotocin-induced mouse model of diabetes, with hyperglycaemia for 8 months, and age-matched control mice, were injected with FITC- ...[more]

PMID: 28755268

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Project description:PurposeRecent studies suggest that photoreceptor cells regulate local inflammation in the retina in diabetes. The purpose of this study was to determine if photoreceptor cells themselves produce inflammatory proteins in diabetes and if soluble factors released by photoreceptors in elevated glucose induce inflammatory changes in nearby cells.MethodsLaser capture microdissection was used to isolate the outer retina (photoreceptors) from the inner retina in nondiabetic and diabetic mice. Diabetes-induced changes in the expression of inflammatory targets were assessed by reverse transcription polymerase chain reaction and immunohistochemistry. Cell culture experiments were carried out to determine if photoreceptors in vitro and ex vivo release soluble mediators that can stimulate nearby cells. Photoreceptor contribution to leukocyte-mediated endothelial cell death was tested using coculture models.ResultsMessenger ribonucleic acid and protein expression levels for inflammatory proteins intercellular adhesion molecule 1 (ICAM1), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX2) were increased in photoreceptors cells in diabetes. In vitro and ex vivo studies show that photoreceptor cells in elevated glucose release mediators that can induce tumor necrosis factor-α in leukocytes and endothelial cells, but not in glia. The soluble mediators released by photoreceptor cells in elevated glucose are regulated by transforming growth factor β-activated kinase 1 and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) signaling. In contrast to enhanced leukocyte-mediated killing of endothelial cells by leukocytes from wild-type diabetic mice, leukocytes from diabetic mice lacking photoreceptor cells (opsin-/-) did not kill endothelial cells.ConclusionsThese data indicate that photoreceptor cells are a source of inflammatory proteins in diabetes, and their release of soluble mediators can contribute to the death of retinal capillaries in diabetes.

Project description:BackgroundMany retinal diseases are associated with vascular dysfunction accompanied by neuroinflammation. We examined the ability of minocycline (Mino), a tetracycline derivative with anti-inflammatory and neuroprotective properties, to prevent vascular permeability and inflammation following retinal ischemia-reperfusion (IR) injury, a model of retinal neurodegeneration with breakdown of the blood-retinal barrier (BRB).MethodsMale Sprague-Dawley rats were subjected to 45 min of pressure-induced retinal ischemia, with the contralateral eye serving as control. Rats were treated with Mino prior to and following IR. At 48 h after reperfusion, retinal gene expression, cellular inflammation, Evan's blue dye leakage, tight junction protein organization, caspase-3 activation, and DNA fragmentation were measured. Cellular inflammation was quantified by flow-cytometric evaluation of retinal tissue using the myeloid marker CD11b and leukocyte common antigen CD45 to differentiate and quantify CD11b+/CD45low microglia, CD11b+/CD45hi myeloid leukocytes and CD11bneg/CD45hi lymphocytes. Major histocompatibility complex class II (MHCII) immunoreactivity was used to determine the inflammatory state of these cells.ResultsMino treatment significantly inhibited IR-induced retinal vascular permeability and disruption of tight junction organization. Retinal IR injury significantly altered mRNA expression for 21 of 25 inflammation- and gliosis-related genes examined. Of these, Mino treatment effectively attenuated IR-induced expression of lipocalin 2 (LCN2), serpin peptidase inhibitor clade A member 3 N (SERPINA3N), TNF receptor superfamily member 12A (TNFRSF12A), monocyte chemoattractant-1 (MCP-1, CCL2) and intercellular adhesion molecule-1 (ICAM-1). A marked increase in leukostasis of both myeloid leukocytes and lymphocytes was observed following IR. Mino treatment significantly reduced retinal leukocyte numbers following IR and was particularly effective in decreasing the appearance of MHCII+ inflammatory leukocytes. Surprisingly, Mino did not significantly inhibit retinal cell death in this model.ConclusionsIR induces a retinal neuroinflammation within hours of reperfusion characterized by inflammatory gene expression, leukocyte adhesion and invasion, and vascular permeability. Despite Mino significantly inhibiting these responses, it failed to block neurodegeneration.

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Photoreceptor cells produce inflammatory products that contribute to retinal vascular permeability in a mouse model of diabetes.

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Photoreceptor cells produce inflammatory products that contribute to retinal vascular permeability in a mouse model of diabetes.

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