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CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes.

ABSTRACT: In this study, the role of CX3CR1 in the progression of diabetic retinopathy (DR) was investigated. The retinas of wild-type (WT), CX3CR1 null (CX3CR1gfp/gfp, KO), and heterozygous (CX3CR1+/gfp, Het) mice were compared in the presence and absence of streptozotocin (STZ)-induced diabetes. CX3CR1 deficiency in STZ-KO increased vascular pathology at 4 months of diabetes, as a significant increase in acellular capillaries was observed only in the STZ-KO group. CX3CR1 deficiency and diabetes had similar effects on retinal neurodegeneration measured by an increase in DNA fragmentation. Retinal vascular pathology in STZ-KO mice was associated with increased numbers of monocyte-derived macrophages in the retina. Furthermore, compared to STZ-WT, STZ-KO mice exhibited increased numbers of inflammatory monocytes in the bone marrow and impaired homing of monocytes to the spleen. The induction of retinal IL-10 expression by diabetes was significantly less in KO mice, and when bone marrow-derived macrophages from KO mice were maintained in high glucose, they expressed significantly less IL-10 and more TNF-? in response to LPS stimulation. These findings support that CX3CR1 deficiency accelerates the development of vascular pathology in DR through increased recruitment of proinflammatory myeloid cells that demonstrate reduced expression of anti-inflammatory IL-10. KEY MESSAGES:• CX3CR1 deletion in STZ-diabetic mice accelerated the onset of diabetic retinopathy (DR). • The early onset of DR was associated with increased retinal cell apoptosis. • The early onset of DR was associated with increased recruitment of bone marrow-derived macrophages to the retina. • Bone marrow-derived macrophages from CX3CR1 KO diabetic mice expressed more TNF-? and less IL-10. • The role of IL-10 in protection from progression of DR is highlighted.

SUBMITTER: Beli E

PROVIDER: S-EPMC5071129 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes.

Beli Eleni E Dominguez James M JM Hu Ping P Thinschmidt Jeffrey S JS Caballero Sergio S Li Calzi Sergio S Luo Defang D Shanmugam Sumathi S Salazar Tatiana E TE Duan Yaqian Y Boulton Michael E ME Mohr Susanna S Abcouwer Steven F SF Saban Daniel R DR Harrison Jeffrey K JK Grant Maria B MB

Journal of molecular medicine (Berlin, Germany) 20160625 11

In this study, the role of CX3CR1 in the progression of diabetic retinopathy (DR) was investigated. The retinas of wild-type (WT), CX3CR1 null (CX3CR1<sup>gfp/gfp</sup>, KO), and heterozygous (CX3CR1<sup>+/gfp</sup>, Het) mice were compared in the presence and absence of streptozotocin (STZ)-induced diabetes. CX3CR1 deficiency in STZ-KO increased vascular pathology at 4 months of diabetes, as a significant increase in acellular capillaries was observed only in the STZ-KO group. CX3CR1 deficiency ...[more]

PMID: 27344677

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Project description:IntroductionHypoxia-induced neuronal damage is the primary cause of cognitive impairment induced by high-altitude exposure. Microglia play a crucial regulatory role in the central nervous system (CNS) homeostasis and synaptic plasticity. M1-type polarized microglia are suspected to be responsible for CNS injury under hypoxic conditions, but the exact molecular mechanism is still unelucidated.MethodsCX3CR1 knock out and wide type mice were exposed to a simulated plateau at 7000 m for 48 h to construct the model of hypobaric hypoxia-induced memory impairment. The memory impairment of mice was assessed by Morris water maze. The dendritic spine density in the hippocampus was examined by Golgi staining. The synapses in the CA1 region and the number of neurons in the DG region were examined by immunofluorescence staining. The synapses in microglia activation and phagocytosis were examined by immunofluorescence. The levels of CX3CL1/CX3CR1 and their downstream proteins were detected. CX3CR1 knockout primary microglia were treated with CX3CL1 combined with 1% O2. The levels of proteins related to microglial polarization, the uptake of synaptosome and phagocytotic ability of microglia were detected.ResultsIn this study, mice exposed to a simulated 7000 m altitude for 48 h developed significant amnesia for recent memories, but no significant change in their anxiety levels was observed. Hypobaric hypoxia exposure (7000 m altitude above sea level for 48 h) resulted in synapse loss in the CA1 region of the hippocampus, but no significant changes occurred in the total number of neurons. Meanwhile, microglia activation, increased phagocytosis of synapses by microglia, and CX3CL1/CX3CR1 signal activation were observed under hypobaric hypoxic exposure. Further, we found that after hypobaric hypoxia exposure, CX3CR1-deficient mice showed less amnesia, less synaptic loss in the CA1 region, and less increase in M1 microglia, compared to their wildtype siblings. CX3CR1-deficient microglia did not exhibit M1-type polarization in response to either hypoxia or CX3CL1 induction. Both hypoxia and CX3CL1 induced the phagocytosis of synapses by microglia through the upregulation of microglial phagocytosis.DiscussionThe current study demonstrates that CX3CL1/CX3CR1 signal mediates the M1-type polarization of microglia under high-altitude exposure and upregulates microglial phagocytosis, which increases the phagocytosis of synapses in the CA1 region of the hippocampus, causing synaptic loss and inducing forgetting.

Project description:AimResults from meta-analyses point to an association between vitamin D deficiency and the onset of diabetic retinopathy (DR). The objectives of the present study were to evaluate the association of vitamin D for the development of DR and to determine the levels of vitamin D associated with a greater risk of DR.MethodsBetween November 2013 and February 2015, we performed a case-control study based on a sample of patients with diabetes in Spain. The study population comprised all patients who had at least one evaluable electroretinogram and recorded levels of 25(OH)D. We collected a series of analytical data: 25(OH)D, 1,25(OH)2D, iPTH, calcium, albumin, and HbA1c. Glycemic control was evaluated on the basis of the mean HbA1c values for the period 2009-2014. A logistic regression analysis was performed to identify the variables associated with DR.ResultsThe final study sample comprised 385 patients, of which 30 (7.8%) had DR. Significant differences were found between patients with and without DR for age (69.54 vs. 73.43), HbA1c (6.68% vs. 7.29%), years since diagnosis of diabetes (10.9 vs. 14.17), level of 25(OH)D (20.80 vs. 15.50 ng/mL), level of 1,25(OH)2D (35.0 vs. 24.5 pg/mL), treatment with insulin (14.9% vs. 56.7%), hypertension (77.7% vs. 100%), cardiovascular events (33.2% vs. 53.3%), and kidney failure (22.0% vs. 43.3%). In the multivariate analysis, the factors identified as independent risk factors for DR were treatment of diabetes (p = 0.001) and 25(OH)D (p = 0.025). The high risk of DR in patients receiving insulin (OR 17.01) was also noteworthy.ConclusionsLevels of 25(OH)D and treatment of diabetes were significantly associated with DR after adjusting for other risk factors. Combined levels of 25(OH)D < 16 ng/mL and levels of 1,25(OH)2D < 29 pg/mL are the variables that best predict the risk of having DR with respect to vitamin D deficiency. The risk factor with the strongest association was the treatment of type 2 diabetes mellitus. This was particularly true for patients receiving insulin, who had a greater risk of DR than those receiving insulin analogues. However, further studies are necessary before a causal relationship can be established.

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CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes.

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CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes.

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