Inhibition of interleukin-6 trans-signaling prevents inflammation and endothelial barrier disruption in retinal endothelial cells

Valle, María Luisa del; Dworshak, Janine; Sharma, Ashok; Ibrahim, Ahmed S.; Al‐Shabrawey, Mohamed; Sharma, Shruti

doi:10.1016/j.exer.2018.09.009

Cited by 73 publications

(78 citation statements)

References 71 publications

(105 reference statements)

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“…Interestingly, protein abundance was decreased in the vitreous of diabetic mice after treatment with sgp130Fc. While this offers support to the vascular leakage hypothesis, as sgp130Fc has been shown to have protective effects on endothelial barrier function, 5 it is also possible that any changes to vascular permeability are instead concordant with an overall decrease in retinal inflammation. Our data demonstrate the protective effects of IL-6 trans-signaling inhibition on the diabetic vitreous proteome, although further studies are needed to delineate the exact mechanism(s) underlying this response.…”

Section: Discussionmentioning

confidence: 69%

“…[1][2][3][4] IL-6 is a pleiotropic cytokine known to be elevated in patients with DR and associated with DR pathology. [5][6][7] Importantly, IL-6 signaling occurs via two different mechanisms: the classical and trans-signaling pathways. 5,8,9 Classical signaling is mediated by the membrane-bound IL-6 receptor; in contrast, IL-6 trans-signaling uses a soluble form of the IL-6 receptor (sIL-6R) and is primarily proinflammatory.…”

mentioning

confidence: 99%

“…10 Our lab has previously demonstrated that sgp130Fc can decrease inflammation, restore oxidative balance, and prevent endothelial barrier dysfunction in retinal endothelial cells. 5,11 Vitreous humor is a gel-like biofluid in the posterior segment of the eye between the lens and the retina. Composed primarily of water, vitreous also contains a variety of macromolecules, both native to the vitreous and from neighboring tissues.…”

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confidence: 99%

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

Robinson

Youngblood

Iyer

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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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.

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Section: Discussionmentioning

confidence: 69%

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confidence: 99%

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confidence: 99%

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

Robinson

Youngblood

Iyer

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…Binding to membrane-bound IL-6 receptor and gp130, IL-6 activates classical IL-6 signaling pathway, which is supposed to be regenerative and protective; while binding to the soluble IL-6 receptor, IL-6 activates IL-6 trans-signaling pathway which is chronic pro-in ammatory and resulting in endothelial cell dysfunction and vascular leakage. [68][69][70] both pathways could be activated in the retina under high glucose. 71,72 Meanwhile, IL-6 is highly correlated with the aqueous level of VEGF in DR. 73 The correlation between VEGF and the pathogenesis of DR is uncontroversial, especially for proliferative DR. 21,74,75 Downstream events of VEGF include survival, proliferation, and permeability.…”

Section: Discussionmentioning

confidence: 96%

A Network Pharmacology Based Analysis of The Potential Mechanisms of Compound Danshen Dripping Pill for Treatment of Diabetic Retinopathy

Zhang¹,

Wang²,

Huang³

et al. 2020

Preprint

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Background: Diabetic retinopathy (DR) has become a worldwide concern in recent years because of the high prevalence and vision-threat. The limited therapies have been in stark contrast to its high prevalence. On top of that, almost all the treatments, like laser, are applied only at the end stage of this disease. However, with the development of network pharmacology, a traditional Chinese medicine (TCM), Compound Danshen Dripping Pill (CDDP), may bring some new insights into the early intervention of DR. Methods: The active compounds and potential targets of CDDP and DR-related targets were collected from the TCMSP, UniProt, GeneCards and OMIM databases. And protein-protein interactions (PPI) information was achieved from the STRING database. The gene enrichment analysis of GO and KEGG was carried out by “clusterProfiler” in R software. The collected data was then used to form network maps of compound-target and PPI, or visualized by the software of Cytoscape. Results: 54 compounds and 50 targets were identified for CDDP against DR. Among the predicted effective compounds, 29 tanshinones from Radix Salviae (Danshen) were identified. And the core targets might be estrogen receptor (ESR1), androgen receptor (AR), caspase-3 (CASP3), Interleukin-6 (IL6) and vascular endothelial growth factor A (VEGFA) in 50 targets. There were 266 significantly correlated biological processes such as steroid hormone response, oxidative stress and apoptosis enriched out. Besides, The 50 targets significantly participate in 97 pathways and mainly enriched in advanced glycation end products (AGE)-receptor for advanced glycation end products (RAGE), fluid shear stress and atherosclerosis, apoptosis and VEGF signal pathway et al.Conclusions: The mechanisms of CDDP for treating DR may involve multi-compound, multi-target and multi-pathway synergistic effects. It may participate in the regulation of steroid hormone response, oxidative stress, apoptosis and hemodynamics in diabetic retina. Tanshinones and luteolin from Radix Salviae were probably responsible for the effectiveness of CDDP on DR.

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“…Gene sets significantly affected by induction of retinal ischemia were related to hypoxia, angiogenesis, and inflammation. Among the inflammatory pathways enriched in our analysis, the IL6, JAK-STAT [42,43], TNFα, and NF-κB pathways [44,45] exacerbate the pathology of retinal disease. However, the expression levels of genes included in each upregulated gene set were not increased equally.…”

Section: Gene Set Enrichment Analysis Of Human Homologsmentioning

confidence: 99%

Gene expression profile analysis of the rabbit retinal vein occlusion model

et al. 2020

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The rabbit retinal vein occlusion (RVO) model is an experimental system that mimics retinal ischemic diseases in humans. The rabbit RVO model is widely used to assess the therapeutic efficacy of various experimental surgical procedures. In the present study, we measured temporal retinal expression of Vegfa, which is known as an ischemic response gene, in rabbit RVO. This analysis revealed that the retinal Vegfa transcriptional response began 7 days after generation of RVO, rather than immediately after induction of ischemia. Next, in order to analyze ischemia-induced changes in gene expression profiles, we performed microarray analysis of day 7 RVO retina versus control retina. The angiogenic regulators Dcn and Mmp1 and pro-inflammatory factors Mmp12 and Cxcl13 were significantly upregulated in RVO retinas. Further, we suggest that epigenetic regulation via the REST/cofactor-complex could contribute to RVO pathology. Among human homologous genes in rabbits, genes associated with hypoxia, angiogenesis, and inflammation were significantly upregulated in RVO retinas. Components of the Tumor necrosis factor-alpha (TNFα) and Nuclear factorkappa B (NF-κB) pathways, which play regulatory roles in angiogenesis and inflammation, were significantly upregulated in RVO, and the expression levels of downstream factors, such as the transcription factor AP-1 and chemokines, were increased. Further, connectivity map analyses suggested that inhibitors of the NF-κB pathway are potential therapeutic agents for retinal ischemic disease. The present study revealed new insights into the pathology of retinal ischemia using the rabbit RVO model, which accurately recapitulates human disease.

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Inhibition of interleukin-6 trans-signaling prevents inflammation and endothelial barrier disruption in retinal endothelial cells

Cited by 73 publications

References 71 publications

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

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

A Network Pharmacology Based Analysis of The Potential Mechanisms of Compound Danshen Dripping Pill for Treatment of Diabetic Retinopathy

Gene expression profile analysis of the rabbit retinal vein occlusion model

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