Dataset Information

Diabetes Induced Alterations in Murine Vitreous Proteome Are Mitigated by IL-6 Trans-Signaling Inhibition.

ABSTRACT:

Purpose

Diabetic retinopathy (DR) is a microvascular complication caused by prolonged hyperglycemia and characterized by leaky retinal vasculature and ischemia-induced angiogenesis. Vitreous humor is a gel-like biofluid in the posterior segment of the eye between the lens and the retina. Disease-related changes are observed in the biochemical constituents of the vitreous, including proteins and macromolecules. Recently, we found that IL-6 trans-signaling plays a significant role in the vascular leakage and retinal pathology associated with DR. Therefore, in this study, comprehensive proteomic profiling of the murine vitreous was performed to identify diabetes-induced alterations and to determine effects of IL-6 trans-signaling inhibition on these changes.

Methods

Vitreous samples from mice were collected by evisceration, and proteomic analyses were performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results

A total of 154 proteins were identified with high confidence in control mice and were considered to be characteristic of healthy murine vitreous fluid. The levels of 72 vitreous proteins were significantly altered in diabetic mice, including several members of heat shock proteins, 14-3-3 proteins, and tubulins. Alterations in 52 out of 72 proteins in diabetic mice were mitigated by IL-6 trans-signaling inhibition.

Conclusions

Proteomic analysis of murine vitreous fluid performed in this study provides important information about the changes caused by diabetes in the ocular microenvironment. These diabetes-induced alterations in the murine vitreous proteome were mitigated by IL-6 trans-signaling inhibition. These findings further support that IL-6 trans-signaling may be an important therapeutic target for the treatment of DR.

SUBMITTER: Robinson R

PROVIDER: S-EPMC7476668 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Diabetes Induced Alterations in Murine Vitreous Proteome Are Mitigated by IL-6 Trans-Signaling Inhibition.

Robinson Rebekah R Youngblood Hannah H Iyer Hersha H Bloom Justin J Lee Tae Jin TJ Chang Luke L Lukowski Zachary Z Zhi Wenbo W Sharma Ashok A Sharma Shruti S

Investigative ophthalmology & visual science 20200901 11

<h4>Purpose</h4>Diabetic retinopathy (DR) is a microvascular complication caused by prolonged hyperglycemia and characterized by leaky retinal vasculature and ischemia-induced angiogenesis. Vitreous humor is a gel-like biofluid in the posterior segment of the eye between the lens and the retina. Disease-related changes are observed in the biochemical constituents of the vitreous, including proteins and macromolecules. Recently, we found that IL-6 trans-signaling plays a significant role in the v ...[more]

PMID: 32870245

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Project description:IntroductionElevated circulating IL-6 levels are associated with poorer outcomes after stroke, and increased serum IL-6 levels are linked to a higher risk of stroke. IL-6 binds to soluble IL-6 receptors (sIL-6R) and subsequently to ubiquitously expressed gp130, initiating proinflammatory trans-signaling. This study tested the hypothesis that inhibiting IL-6 trans-signaling by administering soluble (s) gp130 improves long-term functional outcomes in young mice after stroke.MethodsRecombinant mouse gp130Fc chimera (sgp130) was administered one hour after middle cerebral artery occlusion (MCAO) followed by twice-weekly administration for 2 weeks in mice (8-15 weeks old). Behavioral assessments were done on days 7 and 28 post-MCAO for chronic studies. Flow cytometry was performed on days 3 (blood) and 7 (spleen and brain) to assess IL-6, mIL-6R, and phosphorylated STAT3 expression.ResultsImproved long-term functional outcomes were observed in male, but not female mice. To investigate the differential response in females, ELISA analyses revealed that plasma IL-6 levels increased in both sexes after MCAO, with a more pronounced induction in females. Additionally, circulating sIL-6R levels were significantly higher in females compared to males (p < 0.05) at 24 h post-MCAO. Administering a higher dose of sgp130 (1 mg/kg) to females improved long-term functional outcomes, suggesting that a higher dose is needed to inhibit IL-6 trans-signaling in females effectively. Mechanistically, sgp130 treatment reduced phosphorylated STAT3 expression in brain F4/80 macrophages and increased the expression of mIL-6R on splenic immune cells at day 7 post-MCAO in both sexes.ConclusionThese findings demonstrate that inhibition of IL-6 trans-signaling with gp130Fc improves long-term functional outcomes in both male and female mice, albeit in a dose-dependent manner. This study provides novel insights into potential therapeutic strategies targeting IL-6 signaling pathways following stroke.

Dataset Information

Diabetes Induced Alterations in Murine Vitreous Proteome Are Mitigated by IL-6 Trans-Signaling Inhibition.

Purpose

Methods

Results

Conclusions

Publications

Diabetes Induced Alterations in Murine Vitreous Proteome Are Mitigated by IL-6 Trans-Signaling Inhibition.

Similar Datasets

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