Vascular Associations and Dynamic Process Motility in Perivascular Myeloid Cells of the Mouse Choroid: Implications for Function and Senescent Change

Kumar, Anil; Zhao, Lian; Fariss, Robert N.; McMenamin, Paul G.; Wong, Wai T.

doi:10.1167/iovs.13-13522

Cited by 38 publications

(33 citation statements)

References 49 publications

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“…Real-time movies of the CX3CR1 GFP/+ mouse demonstrate that these macrophage processes are constantly sampling the environment in fulfillment of their role as sentinels and housekeepers. 30 The study also demonstrated that these dendritiform myeloid cells were perivascular and touched the choroidal vessels, 31 which we also observed in human choroid (Supplementary Movie S1). …”

Section: Discussionsupporting

confidence: 67%

Distribution and Quantification of Choroidal Macrophages in Human Eyes With Age-Related Macular Degeneration

McLeod

Bhutto

Edwards

et al. 2016

Invest. Ophthalmol. Vis. Sci.

116

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PurposeIncreasing evidence suggests a role for macrophages in the pathogenesis of age-related macular degeneration (AMD). This study examined choroidal macrophages and their activation in postmortem eyes from subjects with and without AMD.MethodsChoroids were incubated with anti-ionized calcium-binding adapter molecule 1 (anti-IBA1) to label macrophages, anti-human leukocyte antigen-antigen D-related (anti-HLA-DR) as a macrophage activation marker, and Ulex europaeus agglutinin lectin to label blood vessels. Whole mounts were imaged using confocal microscopy. IBA1- and HLA-DR–positive (activated) cells were counted in submacula, paramacula, and nonmacula, and cell volume and sphericity were determined using computer-assisted image analysis.ResultsIn aged control eyes, the mean number of submacular IBA1+ and HLA-DR+ macrophages was 433/mm2 and 152/mm2, respectively. In early AMD eyes, there was a significant increase in IBA1+ and HLA-DR+ cells in submacula compared to those in controls (P = 0.0015 and P = 0.008, respectively). In eyes with neovascular AMD, there were significantly more HLA-DR+ cells associated with submacular choroidal neovascularization (P = 0.001). Mean cell volume was significantly lower (P ≤ 0.02), and sphericity was significantly higher (P ≤ 0.005) in all AMD groups compared to controls.ConclusionsThe average number of IBA1+ macrophages in submacular and paramacular choroid was significantly higher in early/intermediate AMD compared to that in aged controls. HLA-DR+ submacular macrophages were significantly increased in all stages of AMD, and they were significantly more round and smaller in size in the submacular AMD choroid, suggesting their activation. These findings support the concept that AMD is an inflammatory disease.

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Section: Discussionsupporting

confidence: 67%

Distribution and Quantification of Choroidal Macrophages in Human Eyes With Age-Related Macular Degeneration

McLeod

Bhutto

Edwards

et al. 2016

Invest. Ophthalmol. Vis. Sci.

116

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“…D), suggesting that MACs have closer engagement with tube forming cells as part of their supportive role. MACs behavior when cocultured with endothelial cells suggests a potential role for them acting as perivascular macrophages, supporting the endothelium that makes up the vasculature, in part, by sharing close immune‐vascular interactions . This phenomenon is under further investigation.…”

Section: Discussionmentioning

confidence: 89%

The Vasoreparative Function of Myeloid Angiogenic Cells Is Impaired in Diabetes Through the Induction of IL1β

et al. 2018

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Myeloid angiogenic cells (MACs) promote revascularization through the paracrine release of angiogenic factors and have been harnessed as therapeutic cells for many ischemic diseases. However, their proangiogenic properties have been suggested to be diminished in diabetes. This study investigates how the diabetic milieu affects the immunophenotype and function of MACs. Both MACs isolated from diabetic conditions and healthy cells exposed to a diabetic environment were used to determine the potential of MACs as a cell therapy for diabetic‐related ischemia. MACs were isolated from human peripheral blood and characterized alongside proinflammatory macrophages M (LPS + IFNγ) and proangiogenic macrophages M (IL4). Functional changes in MACs in response to high‐d‐glucose were assessed using an in vitro 3D‐tubulogenesis assay. Phenotypic changes were determined by gene and protein expression analysis. Additionally, MACs from type 1 diabetic (T1D) patients and corresponding controls were isolated and characterized. Our evidence demonstrates MACs identity as a distinct macrophage subtype that shares M2 proangiogenic characteristics, but can be distinguished by CD163hi expression. High‐d‐glucose treatment significantly reduced MACs proangiogenic capacity, which was associated with a significant increase in IL1β mRNA and protein expression. Inhibition of IL1β abrogated the antiangiogenic effect induced by high‐d‐glucose. IL1β was also significantly upregulated in MACs isolated from T1D patients with microvascular complications compared to T1D patients without microvascular complications or nondiabetic volunteers. This study demonstrates that Type 1 diabetes and diabetic‐like conditions impair the proangiogenic and regenerative capacity of MACs, and this response is mediated by IL‐1β. Stem Cells 2018;36:834–843

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“…Choroidal vessels are labeled by cardiac perfusion of an aqueous solution containing 1,19-dioctadecyl-3,3,39,39-tetramethylindocarbocyanine perchlorate (DiI, D-282, Invitrogen/Molecular Probes, Carlsbad, CA), a lipophilic dye that incorporates into membranes of endothelial cells revealing the structure of choroidal vessels as previously described (11). Briefly, experimental mice were euthanized by carbon dioxide inhalation and the thoracic cavity opened to expose the heart.…”

Section: Direct Labeling and Visualization Of Choroidal Vesselsmentioning

confidence: 99%

“…Dysfunction in choroidal macrophages has been linked to choroidal vascular alterations detected in aging and in AMD. Altered macrophage morphology and distribution have been correlated with attenuation of the choriocapillaris in the aged mouse choroid (11), and increased density and expression of activation markers in macrophages have been documented with the onset of AMD in human eyes (14), suggesting a causal relationship between macrophage changes and vascular loss. The implication of choroidal vascular loss as a driver of drusen accumulation and RPE disruption in AMD pathogenesis (15)(16)(17) have prompted strategies aimed at maintaining choroidal vascular health and improving vascular supply to the outer retina (18,19), but the intrinsic mechanisms that maintain vascular and RPE integrity in the choroid have not been elucidated, limiting translational efforts.…”

Section: Introductionmentioning

confidence: 99%

“…Under normal conditions, these macrophages are distributed across the entire choroid in the perivascular space in close juxtaposition with choroidal vessels. As they possess ramified cellular processes that demonstrate dynamic behavior, choroidal macrophages can potentially survey the perivascular environment and exchange signals with nearby vascular and RPE cells (11). While activated choroidal macrophages have been implicated in contributing to pathological changes in posterior uveitis (12) and choroidal neovascularization (13), their endogenous functions under healthy conditions are obscure, and if and how they may contribute to homeostasis in the choroid are not understood.…”

Section: Introductionmentioning

confidence: 99%

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Choroid-resident macrophages maintain local vasculature and RPE integrity and spontaneously regenerate following depletion

Yang

Zhao

Campos

et al. 2019

Preprint

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The choroid of the eye provides necessary vascular supply to the outer retina across the retinal pigment epithelial (RPE) layer and is a locus of progressive degenerative change in aging and age-related macular degeneration (AMD). Cellular mechanisms that maintain or compromise choroidal vasculature homeostasis are not well understood, complicating therapeutic efforts. We discover here that pharmacological ablation of macrophages normally resident in the adult mouse choroid via blockade of the CSF1 receptor resulted in progressive thinning of the choroid layer and atrophy of the choriocapillaris. Concurrently, choroidal macrophage ablation also induced structural disorganization of the RPE cell layer, downregulation of RPE visual cycle genes, and altered RPE angiogenic factor expression. Suspension of CSF1R blockade following ablation conversely enabled spontaneous regeneration of the choroidal macrophage population, restoring original macrophage distribution and morphological features. Macrophage repopulation significantly ameliorated the ablation-induced changes in RPE structure and angiogenic factor expression and arrested choroidal vascular atrophy. These findings reveal a previously unsuspected trophic function of resident choroidal macrophages in the maintenance of choroidal vasculature and the RPE layer, suggesting that insufficiency of macrophage function may contribute to age-and AMD-associated pathology. Modulating choroidal macrophage support function can constitute a strategy for therapeutic preservation of the choroid and RPE in AMD prevention and treatment.

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Vascular Associations and Dynamic Process Motility in Perivascular Myeloid Cells of the Mouse Choroid: Implications for Function and Senescent Change

Cited by 38 publications

References 49 publications

Distribution and Quantification of Choroidal Macrophages in Human Eyes With Age-Related Macular Degeneration

Distribution and Quantification of Choroidal Macrophages in Human Eyes With Age-Related Macular Degeneration

The Vasoreparative Function of Myeloid Angiogenic Cells Is Impaired in Diabetes Through the Induction of IL1β

Choroid-resident macrophages maintain local vasculature and RPE integrity and spontaneously regenerate following depletion

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