The Role of Monocytes and Macrophages in Age-Related Macular Degeneration

Grunin, Michelle; Hagbi-Levi, Shira; Chowers, Itay

doi:10.1007/978-1-4614-3209-8_26

Cited by 21 publications

(16 citation statements)

References 44 publications

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“…We cross‐validated the RNA‐seq data from each functional category in AhR −/− and wt mouse RPE‐choroid samples using qPCR (Figure B); primers are listed in Table S3 (see supplementary material). We observed down‐regulation of Gpr124 , a regulator of angiogenesis also known as tumour endothelial factor 5 , down‐regulation of the ECM gene collagen type V α 1 ( Col5a1 ) and up‐regulation of the inflammatory gene chemokine (C–C motif) receptor 1 ( Ccr1 ) . These genes displayed a significant fold change, the direction and magnitude of which was consistent with the RNA‐seq analysis.…”

Section: Resultsmentioning

confidence: 86%

Aryl hydrocarbon receptor knock‐out exacerbates choroidal neovascularization via multiple pathogenic pathways

Choudhary

Kazmin

et al. 2014

The Journal of Pathology

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The aryl hydrocarbon receptor (AhR) is a heterodimeric transcriptional regulator with pleiotropic functions in xenobiotic metabolism and detoxification, vascular development and cancer. Herein, we report a previously undescribed role for the AhR signalling pathway in the pathogenesis of the wet, neovascular subtype of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly in the Western world. Comparative analysis of gene expression profiles of aged AhR−/− and wild-type (wt) mice, using high-throughput RNA sequencing, revealed differential modulation of genes belonging to several AMD-related pathogenic pathways, including inflammation, angiogenesis and extracellular matrix regulation. To investigate AhR regulation of these pathways in wet AMD, we experimentally induced choroidal neovascular lesions in AhR−/− mice and found that they measured significantly larger in area and volume compared to age-matched wt mice. Furthermore, these lesions displayed a higher number of ionized calcium-binding adaptor molecule 1-positive (Iba1+) microglial cells and a greater amount of collagen type IV deposition, events also seen in human wet AMD pathology specimens. Consistent with our in vivo observations, AhR knock-down was sufficient to increase choroidal endothelial cell migration and tube formation in vitro. Moreover, AhR knock-down caused an increase in collagen type IV production and secretion in both retinal pigment epithelial (RPE) and choroidal endothelial cell cultures, increased expression of angiogenic and inflammatory molecules, including vascular endothelial growth factor A (VEGFA) and chemokine (C–C motif) ligand 2 (CCL2) in RPE cells, and increased expression of secreted phosphoprotein 1 (SPP1) and transforming growth factor-β1 (TGFβ1) in choroidal endothelial cells. Collectively, our findings identify AhR as a regulator of multiple pathogenic pathways in experimentally induced choroidal neovascularization, findings that are consistent with a possible role of AhR in wet AMD. The data discussed in this paper have been deposited in NCBI's Gene Expression Omnibus; GEO Submission No. GSE56983, NCBI Tracking System No. 17021116.

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Section: Resultsmentioning

confidence: 86%

Aryl hydrocarbon receptor knock‐out exacerbates choroidal neovascularization via multiple pathogenic pathways

Choudhary

Kazmin

et al. 2014

The Journal of Pathology

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“…Together, these results demonstrated that AMD patients presented an enrichment of Th1 and Th17 cells in PBMCs. [19]. Prior to the induction of retinal lesion, macrophages enriched in the M1 type were found to infiltrate the interphotoreceptor matrix in mice, while in CCR2-deficient mice with no infiltration of macrophages, no retinal lesion was observed [20].…”

Section: Ifn-γ + Th1 Cells and Il-17 + Th17 Cells Were Upregulated Inmentioning

confidence: 99%

Increased Th1/Th17 Responses Contribute to Low-Grade Inflammation in Age-Related Macular Degeneration

Chen

Wang

2017

Cell Physiol Biochem

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Background/Aims: Age-related macular degeneration (AMD) is the primary cause of senior blindness in developed countries. Mechanisms underlying initiation and development of AMD remained known. Methods: We examined the CD4 + T cell compartments and their functions in AMD patients. Results: AMD patients presented significantly higher frequencies of interferon (IFN)-γ-expressing and interleukin (IL)-17-expressing CD4 + T cells than healthy controls. The levels of IFN-γ and IL-17 expression by CD4 + T cells were significantly higher in AMD patients. These IFN-γ-expressing Th1 cells and IL-17-expressing Th17 cells could be selectively enriched by surface CCR3 + and CCR4 + CCR6 + expression, respectively. Th1 and Th17 cells from AMD patients promoted the differentiation of monocytes toward M1 macrophages, which were previously associated with retinal damage. Th1 and Th17 cells also increased the level of MHC class I expression in human retinal pigment epithelial (RPE)-1 cells, while Th1 cells increased the frequency of MHC class II-expressing RPE-1 cells. These proinflammatory effects were partly, but not entirely, induced by the secretion of IFN-γ and IL-17. Conclusions: This study demonstrated an enrichment of Th1 cells and Th17 cells in AMD patients. These Th1 and Th17 cells possessed proinflammatory roles in an IFN-γ-and IL-17-dependent fashion, and could potentially serve as therapeutic targets.

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“…While a wide body of knowledge exists on the role of macrophages in disease of the outer retina 18,19 and experimental data are available, 20 little is known about the dynamics of macrophages during RVO, a chronic disease of the inner retina characterized by hypoxia. We and others have previously described a mouse model of experimental branch retinal vein occlusion (BRVO).…”

mentioning

confidence: 99%

Microglia Activation and Recruitment of Circulating Macrophages During Ischemic Experimental Branch Retinal Vein Occlusion

Ebneter

Kokona

Schneider

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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METHODS. Experimental BRVO was induced in Balb/c mice and histologic changes were studied. Tissue hypoxia was visualized using pimonidazole hydrochloride. Monocyte-derived retinal cells were quantified using histology and flow cytometry. To investigate the dynamics of invading blood-borne macrophages, chimera mice were generated using bone marrow grafts from Cx3cr1 (gfp/gfp) mice to rescue lethally irradiated wild-type BALB/c mice. Longitudinal in vivo imaging was performed to monitor cell invasion. The levels of proinflammatory cytokines in the retina were quantified by quantitative real-time PCR.RESULTS. Histology showed disruption of tissue architecture and temporary swelling with marked hypoxia coinciding with increased VEGF-A and hypoxia inducible factor-1a (HIF-1a) expression and elevation of proinflammatory cytokines within 3 days after experimental BRVO, followed by thinning of the inner retinal layers at later time points. Proinflammatory cytokine levels were elevated. Activation of resident retinal microglia and recruitment of circulating macrophages in areas of hypoxic retina were evident early after the insult and peaked at day 7, remaining elevated for up to 28 days. Flow cytometry showed upregulation of CD68 and major histocompatibility complex class-II (MHC-II) expression at day 3, culminating at day 7.CONCLUSIONS. Experimental BRVO causes hypoxia and breakdown of the inner blood-retina barrier, followed by activation of microglia and invasion of macrophages from the systemic circulation. Consequently, treatments targeting microglia activation or macrophage recruitment might potentially mitigate the sequelae and attenuate degenerative changes induced by retinal vein occlusion.

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The Role of Monocytes and Macrophages in Age-Related Macular Degeneration

Cited by 21 publications

References 44 publications

Aryl hydrocarbon receptor knock‐out exacerbates choroidal neovascularization via multiple pathogenic pathways

Aryl hydrocarbon receptor knock‐out exacerbates choroidal neovascularization via multiple pathogenic pathways

Increased Th1/Th17 Responses Contribute to Low-Grade Inflammation in Age-Related Macular Degeneration

Microglia Activation and Recruitment of Circulating Macrophages During Ischemic Experimental Branch Retinal Vein Occlusion

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