<scp>IL</scp>‐17 signaling induces <scp>iNOS</scp>+ microglia activation in retinal vascular diseases

Zhou, Tian; Liang, Yan; Yang, Ziqi; Ni, Biyan; Zhu, Xiaowei; Huang, Zijing; Xu, Huiyi; Feng, Qiumin; Lin, Xiaojing; Liu, Xialin

doi:10.1002/glia.24063

“…One study suggests that CRS may decrease the size of cerebral vessels and increases blood-brain barrier (BBB) permeability, which eventually promotes leakage of plasma immunoglobulins across the BBB into perivascular and parenchymal spaces [ 55 ]. We have reported that repeated social defeat stress could induce microglia activation [ 1 ], which subsequently causes cerebrovascular inflammation [ 56 , 57 ]. In addition, mental stress is found to elevate levels of circulating proinflammatory cytokines and glucocorticoids, which potentially impacts the brain vessels by altering the central inflammatory state via glucocorticoid feedback to the brain [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Induced Inflammatory and Oxidative Markers in Cerebral Microvasculature by Mentally Depressive Stress

Zhu

¹

,

Haddad

²

,

Yun

³

et al. 2023

Mediators of Inflammation

2

1

0

View full text Add to dashboard Cite

Background. Cerebrovascular disease (CVD) is recognized as the leading cause of permanent disability worldwide. Depressive disorders are associated with increased incidence of CVD. The goal of this study was to establish a chronic restraint stress (CRS) model for mice and examine the effect of stress on cerebrovascular inflammation and oxidative stress responses. Methods. A total of forty 6-week-old male C57BL/6J mice were randomly divided into the CRS and control groups. In the CRS group ( n = 20 ), mice were placed in a well-ventilated Plexiglas tube for 6 hours per day for 28 consecutive days. On day 29, open field tests (OFT) and sucrose preference tests (SPT) were performed to assess depressive-like behaviors for the two groups ( n = 10 /group). Macrophage infiltration into the brain tissue upon stress was analyzed by measuring expression of macrophage marker (CD68) with immunofluorescence in both the CRS and control groups ( n = 10 /group). Cerebral microvasculature was isolated from the CRS and controls ( n = 10 /group). mRNA and protein expressions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1), and macrophage chemoattractant protein-1 (MCP-1) in the brain vessels were measured by real-time PCR and Western blot ( n = 10 /group). Reactive oxygen species (ROS), hydrogen peroxide (H2O2), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activities were quantified by ELISA to study the oxidative profile of the brain vessels ( n = 10 /group). Additionally, mRNA and protein expressions of NOX subunits (gp91phox, p47phox, p67phox, and p22phox) in the cerebrovascular endothelium were analyzed by real-time PCR and Western blot ( n = 10 /group). Results. CRS decreased the total distances ( p < 0.05 ) and the time spent in the center zone in OFT ( p < 0.001 ) and sucrose preference test ratio in SPT ( p < 0.01 ). Positive ratio of CD68+ was increased with CRS in the entire region of the brain ( p < 0.001 ), reflecting increased macrophage infiltration. CRS increased the expression of inflammatory factors and oxidative stress in the cerebral microvasculature, including TNF-α ( p < 0.001 ), IL-1β ( p < 0.05 ), IL-6 ( p < 0.05 ), VCAM-1 ( p < 0.01 ), MCP-1 ( p < 0.01 ), ROS ( p < 0.001 ), and H2O2 ( p < 0.001 ). NADPH oxidase (NOX) was activated by CRS ( p < 0.01 ), and mRNA and protein expressions of NOX subunits (gp91phox, p47phox, p67phox, and p22phox) in brain microvasculature were found to be increased. Conclusions. To our knowledge, this is the first study to demonstrate that CRS induces depressive stress and causes inflammatory and oxidative stress responses in the brain microvasculature.

show abstract

“…Other studies have confirmed that intercellular adhesion molecule-1 mediates the migration of Th17 cells in human retinal vascular endothelial cells ( 44 ). The co-staining of IL-17, RORγt and CD4 in the retina of diabetic retinopathy showed that Th17 cells infiltrated and damaged the retina during the formation of DR ( 45 ). The above results are consistent with the top five GO functional enrichment results in this study: the top five terms enriched by DETh17RGs in this study are all related to cell movement, migration and regulation.…”

Section: Discussionmentioning

confidence: 99%

Gene Biomarkers Related to Th17 Cells in Macular Edema of Diabetic Retinopathy: Cutting-Edge Comprehensive Bioinformatics Analysis and In Vivo Validation

Jing

¹

,

Zhou

²

2022

View full text Add to dashboard Cite

BackgroundPrevious studies have shown that T-helper 17 (Th17) cell-related cytokines are significantly increased in the vitreous of proliferative diabetic retinopathy (PDR), suggesting that Th17 cells play an important role in the inflammatory response of diabetic retinopathy (DR), but its cell infiltration and gene correlation in the retina of DR, especially in diabetic macular edema (DME), have not been studied.MethodsThe dataset GSE160306 was downloaded from the Gene Expression Omnibus (GEO) database, which contains 9 NPDR samples and 10 DME samples. ImmuCellAI algorithm was used to estimate the abundance of Th17 cells in 24 kinds of infiltrating immune cells. The differentially expressed Th17 related genes (DETh17RGs) between NPDR and DME were documented by difference analysis and correlation analysis. Through aggregate analyses such as gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis, a protein-protein interaction (PPI) network was constructed to analyze the potential function of DETh17RGs. CytoHubba plug-in algorithm, Lasso regression analysis and support vector machine recursive feature elimination (SVM-RFE) were implemented to comprehensively identify Hub DETh17RGs. The expression archetypes of Hub DETh17RGs were further verified in several other independent datasets related to DR. The Th17RG score was defined as the genetic characterization of six Hub DETh17RGs using the GSVA sample score method, which was used to distinguish early and advanced diabetic nephropathy (DN) as well as normal and diabetic nephropathy. Finally, real-time quantitative PCR (qPCR) was implemented to verify the transcription levels of Hub DETh17RGs in the STZ-induced DR model mice (C57BL/6J).Results238 DETh17RGs were identified, of which 212 genes were positively correlated while only 26 genes were negatively correlated. Six genes (CD44, CDC42, TIMP1, BMP7, RHOC, FLT1) were identified as Hub DETh17RGs. Because DR and DN have a strong correlation in clinical practice, the verification of multiple independent datasets related to DR and DN proved that Hub DETh17RGs can not only distinguish PDR patients from normal people, but also distinguish DN patients from normal people. It can also identify the initial and advanced stages of the two diseases (NPDR vs DME, Early DN vs Advanced DN). Except for CDC42 and TIMP1, the qPCR transcription levels and trends of other Hub DETh17RGs in STZ-induced DR model mice were consistent with the human transcriptome level in this study.ConclusionThis study will improve our understanding of Th17 cell-related molecular mechanisms in the progression of DME. At the same time, it also provides an updated basis for the molecular mechanism of Th17 cell crosstalk in the eye and kidney in diabetes.

show abstract

“…For instance, cluster 1 samples interact with microglia through IL17, VEGF, and POSTN, or with macrophage through TNFSF12, or with CD8 T cells through F2R more active than cluster 2 samples. IL17 can activate microglia ( 70 , 71 ) and promote GBM progression ( 72 , 73 ). The connection between POSTN and regulating TGF-β1, HIF-1α, and VEGFA expression has been confirmed, which can affect GBM progression and macrophages ( 74 , 75 ).…”

Section: Discussionmentioning

confidence: 99%

Tumor-secreted lactate contributes to an immunosuppressive microenvironment and affects CD8 T-cell infiltration in glioblastoma

Wang

¹

,

Dai

²

,

Zhang

³

et al. 2023

View full text Add to dashboard Cite

IntroductionGlioblastoma is a malignant brain tumor with poor prognosis. Lactate is the main product of tumor cells, and its secretion may relate to immunocytes’ activation. However, its role in glioblastoma is poorly understood. MethodsThis work performed bulk RNA-seq analysis and single cell RNA-seq analysis to explore the role of lactate in glioblastoma progression. Over 1400 glioblastoma samples were grouped into different clusters according to their expression and the results were validated with our own data, the xiangya cohort. Immunocytes infiltration analysis, immunogram and the map of immune checkpoint genes’ expression were applied to analyze the potential connection between the lactate level with tumor immune microenvironment. Furthermore, machine learning algorithms and cell-cell interaction algorithm were introduced to reveal the connection of tumor cells with immunocytes. By co-culturing CD8 T cells with tumor cells, and performing immunohistochemistry on Xiangya cohort samples further validated results from previous analysis.DiscussionIn this work, lactate is proved that contributes to glioblastoma immune suppressive microenvironment. High level of lactate in tumor microenvironment can affect CD8 T cells’ migration and infiltration ratio in glioblastoma. To step further, potential compounds that targets to samples from different groups were also predicted for future exploration.

show abstract

IL‐17 signaling induces iNOS+ microglia activation in retinal vascular diseases

Cited by 23 publications

References 52 publications

Induced Inflammatory and Oxidative Markers in Cerebral Microvasculature by Mentally Depressive Stress

Induced Inflammatory and Oxidative Markers in Cerebral Microvasculature by Mentally Depressive Stress

Gene Biomarkers Related to Th17 Cells in Macular Edema of Diabetic Retinopathy: Cutting-Edge Comprehensive Bioinformatics Analysis and In Vivo Validation

Tumor-secreted lactate contributes to an immunosuppressive microenvironment and affects CD8 T-cell infiltration in glioblastoma

Contact Info

Product

Resources

About