A potential novel therapeutic target in diabetic retinopathy: a chemokine receptor (CCR2/CCR5) inhibitor reduces retinal vascular leakage in an animal model

Monickaraj, Finny; Oruganti, Sreenivasa Rao; McGuire, Paul; Das, Arup

doi:10.1007/s00417-020-04884-5

Cited by 22 publications

(12 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously, Zeng et al (45) also found cells in FVMs were heavily labeled with microglial markers. Besides, in experimental model of DR (46), elimination of microglia and macrophages reduced retinal vascular leakage of DR (46). Of note, we not only verified the microglia as the major cell population, but further found that the activation of microglia (MG(1) subtype) was strongly associated with FVM formation.…”

Section: Discussionsupporting

confidence: 67%

Single-Cell Transcriptomics Reveals Novel Role of Microglia in Fibrovascular Membrane of Proliferative Diabetic Retinopathy

Mao

Chen

et al. 2022

Diabetes

View full text Add to dashboard Cite

Vitreous fibrovascular membranes (FVMs), the hallmark of proliferative diabetic retinopathy (PDR), cause retinal hemorrhage, detachment and eventually blindness. However, little is known about the pathophysiology of FVM. In this study, we employed single-cell RNA sequencing on surgically harvested PDR-FVMs and generated a comprehensive cell atlas of FVM. A total of 8 cellular compositions were identified, with microglia as the major cell population. We identified a GPNMB+ subpopulation of microglia, which presented both profibrotic and fibrogenic properties. Pseudotime analysis further revealed the profibrotic microglia was uniquely differentiated from retina-resident microglia and expanded in PDR setting. Ligand-receptor interactions between the profibrotic microglia and cytokines upregulated in PDR vitreous implicated the involvement of several pathways, including CCR5, IFNGR1 and CD44 signaling, in the microglial activation within PDR microenvironment. Collectively, our description of the novel microglia phenotypes in PDR-FVM may offer new insight into the cellular and molecular mechanism underlying the pathogenesis of DR, as well as potential signaling pathways amenable to disease-specific intervention.

show abstract

Section: Discussionsupporting

confidence: 67%

Single-Cell Transcriptomics Reveals Novel Role of Microglia in Fibrovascular Membrane of Proliferative Diabetic Retinopathy

Mao

Chen

et al. 2022

Diabetes

View full text Add to dashboard Cite

show abstract

“…Recently, researchers have found that chemokines and their receptors are involved in the development of retinopathy [ 13 , 26 ]. For example, CCL5 is a potential systemic biomarker, and administration of a CCR2/CCR5 inhibitor (TAK-779) significantly reduces retinal vascular leakage in DR [ 27 , 28 ]. A CCR3 inhibitor (AKST4290) combined with intravitreal anti-VEGF injections has been used to treat exudative age-related macular degeneration (AMD) [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

CXCL1-CXCR2 signalling mediates hypertensive retinopathy by inducing macrophage infiltration

et al. 2022

View full text Add to dashboard Cite

“…TAK-779, a dual CCR2/CCR5 inhibitor, significantly reduced retinal vascular permeability in diabetic mice [ 181 ]. TAK-779 also decreased infiltration of macrophage/microglia, reduced the expressions of ICAM-1 and stromal cell-derived factor 1 (SDF-1), and restored zonula occludens-1 (ZO-1) in diabetic mouse retina [ 181 ]. Targeting CCR2/CCR5 might provide a novel strategy for DME management.…”

Section: Therapeutic Strategies For Dmementioning

confidence: 99%

Diabetic Macular Edema: Current Understanding, Molecular Mechanisms and Therapeutic Implications

Zhang

Zhang²,

Zhang

et al. 2022

Cells

View full text Add to dashboard Cite

Diabetic retinopathy (DR), with increasing incidence, is the major cause of vision loss and blindness worldwide in working-age adults. Diabetic macular edema (DME) remains the main cause of vision impairment in diabetic patients, with its pathogenesis still not completely elucidated. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of DR and DME. Currently, intravitreal injection of anti-VEGF agents remains as the first-line therapy in DME treatment due to the superior anatomic and functional outcomes. However, some patients do not respond satisfactorily to anti-VEGF injections. More than 30% patients still exist with persistent DME even after regular intravitreal injection for at least 4 injections within 24 weeks, suggesting other pathogenic factors, beyond VEGF, might contribute to the pathogenesis of DME. Recent advances showed nearly all the retinal cells are involved in DR and DME, including breakdown of blood-retinal barrier (BRB), drainage dysfunction of Müller glia and retinal pigment epithelium (RPE), involvement of inflammation, oxidative stress, and neurodegeneration, all complicating the pathogenesis of DME. The profound understanding of the changes in proteomics and metabolomics helps improve the elucidation of the pathogenesis of DR and DME and leads to the identification of novel targets, biomarkers and potential therapeutic strategies for DME treatment. The present review aimed to summarize the current understanding of DME, the involved molecular mechanisms, and the changes in proteomics and metabolomics, thus to propose the potential therapeutic recommendations for personalized treatment of DME.

show abstract

A potential novel therapeutic target in diabetic retinopathy: a chemokine receptor (CCR2/CCR5) inhibitor reduces retinal vascular leakage in an animal model

Cited by 22 publications

References 24 publications

Single-Cell Transcriptomics Reveals Novel Role of Microglia in Fibrovascular Membrane of Proliferative Diabetic Retinopathy

Single-Cell Transcriptomics Reveals Novel Role of Microglia in Fibrovascular Membrane of Proliferative Diabetic Retinopathy

CXCL1-CXCR2 signalling mediates hypertensive retinopathy by inducing macrophage infiltration

Diabetic Macular Edema: Current Understanding, Molecular Mechanisms and Therapeutic Implications

Contact Info

Product

Resources

About