The Metaflammatory and Immunometabolic Role of Macrophages and Microglia in Diabetic Retinopathy

Wu, Hong-Lian; Wang, Mengqi; Li, Xiaorong; Shao, Yan

doi:10.1007/s13577-021-00580-6

Cited by 28 publications

(11 citation statements)

References 97 publications

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“…These processes rely on external factors including transcription factors, intrinsic-signaling pathways, cytokines, and metabolic adaptation (14). Previous studies have demonstrated the key signals involved in M2 macrophage polarization in DR (10,15,16). A recent study also showed that M2 Macrophages are the major immune cells that involved in the immune response of retinal neovascularization in the rat model with ischemic retinopathy (17).…”

Section: Introductionmentioning

confidence: 99%

Exploring the Immune Infiltration Landscape and M2 Macrophage-Related Biomarkers of Proliferative Diabetic Retinopathy

Meng

Chen

et al. 2022

Front. Endocrinol.

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BackgroundsDiabetic retinopathy (DR), especially proliferative diabetic retinopathy (PDR), is the major cause of irreversible blindness in the working-age population. Increasing evidence indicates that immune cells and the inflammatory microenvironment play an important role during PDR development. Herein, we aim to explore the immune landscape of PDR and then identify potential biomarkers correlated with specific infiltrating immune cells.MethodsWe mined and re-analyzed PDR-related datasets from the Gene Expression Omnibus (GEO) database. Using the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm, we investigated the infiltration of 22 types of immune cells in all selected samples; analyses of differences and correlations between infiltrating cells were used to reveal the immune landscape of PDR. Thereafter, weighted gene co-expression network analysis (WGCNA) and differential expression analysis were applied to identify the hub genes on M2 macrophages that may affect PDR progression.ResultsSignificant differences were found between infiltration levels of immune cells in fibrovascular membranes (FVMs) from PDR and normal retinas. The percentages of follicular helper T cells, M1 macrophages, and M2 macrophages were increased significantly in FVMs. Integrative analysis combining the differential expression and co-expression revealed the M2 macrophage-related hub genes in PDR. Among these, COL5A2, CALD1, COL6A3, CORO1C, and CALU showed increased expression in FVM and may be potential biomarkers for PDR.ConclusionsOur findings provide novel insights into the immune mechanisms involved in PDR. COL5A2, CALD1, COL6A3, CORO1C, and CALU are M2 macrophage-related biomarkers, further study of these genes could inform novel ideas and basis for the understanding of disease progression and targeted treatment of PDR.

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Section: Introductionmentioning

confidence: 99%

Exploring the Immune Infiltration Landscape and M2 Macrophage-Related Biomarkers of Proliferative Diabetic Retinopathy

Meng

Chen

et al. 2022

Front. Endocrinol.

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“…CD11c is expressed in activated microglia, and they have the characteristics of proliferation and migration (74). The expression of CD11c was also up-regulated in M1 macrophages of DR (75). Upregulation of the expression of CD11c on monocytes was also detected in circulating blood of diabetic patients (76).…”

Section: Discussionmentioning

confidence: 99%

CD8+T Cell-Related Gene Biomarkers in Macular Edema of Diabetic Retinopathy

Jing

Zhou

2022

Front. Endocrinol.

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BackgroundCD8+T lymphocytes have a strong pro-inflammatory effect in all parts of the tissue, and some studies have demonstrated that its concentration in the vitreous increased significantly, suggesting that CD8+T cells play a pivotal role in the inflammatory response of diabetic retinopathy (DR). However, the infiltration of CD8+T cells in the DR retina, especially in diabetic macular edema (DME), and its related genes are still unclear.MethodsDownload the GSE16036 dataset from the Gene Expression Omnibus (GEO) database. The ImmuCellAI program was performed to evaluate the abundance of 24 immune cells including CD8+T cells. The CD8+T cell-related genes (DECD8+TRGs) between non-proliferative diabetic retinopathy (NPDR) and DME were detected via difference analysis and correlation analysis. Enrichment analysis and protein-protein interaction (PPI) network mapping were implemented to explore the potential function of DECD8+TRGs. Lasso regression, support vector machine recursive feature elimination (SVM-RFE), CytoHubba plug-in and MCODE plug-in in Cytoscape software, and Weighted Gene Co-Expression Network Analysis (WGCNA) were performed to comprehensively analyze and obtain Hub DECD8+TRGs. Hub DECD8+TRGs expression patterns were further validated in other two DR-related independent datasets. The CD8+TRG score was defined as the genetic characterization of Hub DECD8+TRGs using the GSVA sample scoring method, which can be administered to distinguish early and advanced diabetic nephropathy (DN) as well as normal and DN. Finally, the transcription level of DECD8+TRGs in DR model mouse were verified by quantitative real-time PCR (qPCR).ResultsA total of 371 DECD8+TRGs were identified, of which 294 genes were positively correlated and only 77 genes were negatively correlated. Eight genes (IKZF1, PTPRC, ITGB2, ITGAX, TLR7, LYN, CD74, SPI1) were recognized as Hub DECD8+TRGs. DR and DN, which have strong clinical correlation, have been proved to be associated with CD8+T cell-related hub genes by multiple independent data sets. Hub DECD8+TRGs can not only distinguish PDR from normal and DN from normal, but also play a role in the early and progressive stages of the two diseases (NPDR vs DME, Early DN vs Advanced DN). The qPCR transcription level and trend of Hub DECD8+TRGs in DR mouse model was basically the same as that in human transcriptome.ConclusionThis study not only increases our understanding of the molecular mechanism of CD8+T cells in the progression of DME, but also expands people’s cognitive vision of the molecular mechanism of crosstalk of CD8+T cells in the eyes and kidneys of patients with diabetes.

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“…However, in the wake of continuous insults, such as it is in diabetes and retinopathy, activated microglia secrete multiple pro-inflammatory cytokines and mediators that overwhelm the reparative capacity of microglia and are detrimental to nearby retinal neurons [ 63 ]. Among the two known phenotypes of microglia, M1 has a pro-inflammatory role when activated for a long time, while M2 has a pro-resolving role, by favoring tissue repair [ 64 ]. Therefore, controlling M1 microglia activation could be helpful for DR management.…”

Section: Discussionmentioning

confidence: 99%

Systemic Beta-Hydroxybutyrate Affects BDNF and Autophagy into the Retina of Diabetic Mice

Trotta

Gesualdo

Herman

et al. 2022

IJMS

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Background: Diabetic retinopathy (DR) is a neurovascular disease, characterized by a deficiency of brain-derived neurotrophic factor (BDNF), a regulator of autophagy. Beta-hydroxybutyrate (BHB), previously reported as a protective agent in DR, has been associated with BDNF promotion. Here, we investigated whether systemic BHB affects the retinal levels of BDNF and local autophagy in diabetic mice with retinopathy; Methods: C57BL/6J mice were administered with intraperitoneal (i.p.) streptozotocin (STZ) (75 mg/kg) injection to develop diabetes. After 2 weeks, they received i.p. injections of BHB (25–50–100 mg/kg) twice a week for 10 weeks. Retinal samples were collected in order to perform immunofluorescence, Western blotting, and ELISA analysis; Results: BHB 50 mg/kg and 100 mg/kg significantly improved retinal BDNF levels (p < 0.01) in diabetic mice. This improvement was negatively associated with autophagosome–lysosome formations (marked by LC3B and ATG14) and to higher levels of connexin 43 (p < 0.01), a marker of cell integrity. Moreover, BHB administration significantly reduced M1 microglial activation and autophagy (p < 0.01); Conclusions: The systemic administration of BHB in mice with DR improves the retinal levels of BDNF, with the consequent reduction of the abnormal microglial autophagy. This leads to retinal cell safety through connexin 43 restoration.

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The Metaflammatory and Immunometabolic Role of Macrophages and Microglia in Diabetic Retinopathy

Cited by 28 publications

References 97 publications

Exploring the Immune Infiltration Landscape and M2 Macrophage-Related Biomarkers of Proliferative Diabetic Retinopathy

Exploring the Immune Infiltration Landscape and M2 Macrophage-Related Biomarkers of Proliferative Diabetic Retinopathy

CD8+T Cell-Related Gene Biomarkers in Macular Edema of Diabetic Retinopathy

Systemic Beta-Hydroxybutyrate Affects BDNF and Autophagy into the Retina of Diabetic Mice

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