Macrophage Depletion Diminishes Lesion Size and Severity in Experimental Choroidal Neovascularization

Espinosa‐Heidmann, Diego G.; Suñer, Iván J.; Hernandez, E.; Monroy, Dagoberto; Csaky, Karl G.; Cousins, Scott W.

doi:10.1167/iovs.03-0038

Cited by 357 publications

(312 citation statements)

References 33 publications

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“…It has been reported that up-regulated macrophage and inflammatory cell function may worsen or exacerbate already existing inflammatory lesions [Espinosa-Heidmann et al, 2003]. This up-regulation can be spurred by both CCL2 and VEGF expression.…”

Section: Discussionmentioning

confidence: 99%

An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation

Bojanowski

Shen

Chew

et al. 2006

Environ and Mol Mutagen

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Age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness among the elderly in Western countries. Genetic factors, age, cigarette smoking, nutrition, and exposure to light have been identified as AMD risk factors. In this study, we investigated the association between ApoE C112R/R158C single nucleotide polymorphisms (which determine the E2, E3, and E4 isoforms) and age-related macular degeneration (AMD), and the mechanism underlying the association. Genomic DNA was extracted from 133 clinically screened controls, 94 volunteers with a younger mean age, 120 patients with advanced AMD, and 40 archived ocular AMD slides for single nucleotide polymorphism typing. The effects of recombinant ApoE isoforms on CCL2 (a chemokine), CX3CR1 (a chemokine receptor), and VEGF (a cytokine) expression in cultured human retinal pigment epithelium (RPE) cells were tested and serum cholesterol profiles of the clinically screened subjects were analyzed. ApoE112R (E4) distribution differed significantly between AMD patients and controls. ApoE112R allele frequency was 10.9% in the AMD group when compared with 16.5% in the younger controls and 18.8% in the clinically screened controls. The pathologically diagnosed archived AMD cases had the lowest allele frequency of 5%. No significant differences in ApoE158C (E2) distribution were observed among the groups. A meta-analysis of 8 cohorts including 4,289 subjects showed a strong association between AMD and 112R, but not 158C. In vitro studies found that recombinant ApoE suppresses CCL2 and VEGF expression in RPE cells. However, the E4 isoform showed more suppression than E3 in both cases. These results further confirm the association between ApoE112R and a decreased risk of AMD development. The underlying mechanisms may involve differential regulation of both CCL2 and VEGF by the ApoE isoforms.

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Section: Discussionmentioning

confidence: 99%

An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation

Bojanowski

Shen

Chew

et al. 2006

Environ and Mol Mutagen

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“…Although the molecular bases of these diseases may be diverse, the deposits contain many shared molecular constituents that are attributable, in part, to local inflammation and activation of the complement cascade, a key element of the innate immune system in host defense. Drusen are the hallmark deposits associated with early AMD (eAMD), and recent studies have implicated local inflammation and activation of the complement cascade in their formation (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Drusen contain complement activators, inhibitors, activation-specific complement fragments, and terminal pathway components, including the membrane attack complex (MAC).…”

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confidence: 99%

A common haplotype in the complement regulatory gene factor H ( HF1/CFH ) predisposes individuals to age-related macular degeneration

Hageman

Anderson

Johnson

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

1,791

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Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of AMD. Here, we show that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium. Because previous linkage analyses identified chromosome 1q25-32, which harbors the factor H gene (HF1͞CFH), as an AMD susceptibility locus, we analyzed HF1 for genetic variation in two independent cohorts comprised of Ϸ900 AMD cases and 400 matched controls. We found association of eight common HF1 SNPs with AMD; two common missense variants exhibit highly significant associations (I62V, 2 ‫؍‬ 26.1 and P ‫؍‬ 3.2 ؋ 10 ؊7 and Y402H, 2 ‫؍‬ 54.4 and P ‫؍‬ 1.6 ؋ 10 ؊13 ). Haplotype analysis reveals that multiple HF1 variants confer elevated or reduced risk of AMD. One common at-risk haplotype is present at a frequency of 50% in AMD cases and 29% in controls [odds ratio (OR) ‫؍‬ 2.46, 95% confidence interval (1.95-3.11)]. Homozygotes for this haplotype account for 24% of cases and 8% of controls [OR ‫؍‬ 3.51, 95% confidence interval (2.13-5.78)]. Several protective haplotypes are also identified (OR ‫؍‬ 0.44 -0.55), further implicating HF1 function in the pathogenetic mechanisms underlying AMD. We propose that genetic variation in a regulator of the alternative complement pathway, when combined with a triggering event, such as infection, underlie a major proportion of AMD in the human population.A ge-related macular degeneration (AMD) is the leading cause of irreversible vision loss (1, 2), affecting Ϸ50 million individuals worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes that occur at the interface between the neural retina and the underlying choroid. At this location are the retinal photoreceptors, the retinal pigmented epithelium (RPE), a basement membrane complex known as Bruch's membrane (BM) and a network of choroidal capillaries.The prevailing view is that AMD is a complex disorder stemming from the interaction of multiple genetic and environmental risk factors (3,4). Familial aggregation studies indicate that a genetic contribution can be identified in up to 25% of the cases (5). Thus, AMD appears to be a product of the interaction between multiple susceptibility loci rather than a collection of single-gene disorders. The number of loci involved, the attributable risk conferred, and the interactions between various loci remain obscure.

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“…Finally, do the conflicting results of previous studies of the role of macrophages in various models of NVAMD accurately mimic the disease in humans? [95][96][97][98] TGF-β is a multi-functional cytokine and is usually secreted in its latent form, thus allowing for sustained release throughout the repair process. 76 It can both stimulate and inhibit mitogenesis and stimulate angiogenesis, fibroblast differentiation, and matrix deposition.…”

Section: Subretinal Neovascularisationmentioning

confidence: 99%

The stereotypical molecular cascade in neovascular age-related macular degeneration: the role of dynamic reciprocity

Kent

2015

Eye

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This review summarises our current understanding of the molecular basis of subretinal neovascularisation (SRNV) in age-related macular degeneration (AMD). The term neovascular AMD (NVAMD) is derived from the dominant early clinical features of haemorrhage, fluid, and lipid in the subretinal space (SRS) and the historical role of fluorescein angiography in detecting the presence of NV tissue. However, at the cellular level, SRNV resembles an aberrant but stereotypical tissue repair response that incorporates both an early inflammatory phase and a late fibrotic phase in addition to the neovascular (NV) component that dominates the early clinical presentation. This review will seek not only to highlight the important molecules involved in each of these components but to demonstrate that the development of SRNV has its origins in the earliest events in non-NV AMD pathogenesis. Current evidence suggests that this early-stage pathogenesis is characterised by complementmediated immune dysregulation, leading to a state of chronic inflammation in the retinal pigment epithelium/Bruch's membrane/ choriocapillaris complex. These initial events can be seamlessly and inextricably linked to late-stage development of SRNV in AMD by the process of dynamic reciprocity (DyR), the ongoing bidirectional communication between cells, and their surrounding matrix. Moreover, this correlation between disease onset and eventual outcome is reflected in the temporal and spatial correlation between chronic inflammation, NV, and fibrosis within the reparative microenvironment of the SRS. In summary, the downstream consequences of the earliest dysfunctional molecular events in AMD can result in the late-stage entity we recognize clinically as SRNV and is characterized by a spectrum of predictable, related, and stereotypical processes referred to as DyR.

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Macrophage Depletion Diminishes Lesion Size and Severity in Experimental Choroidal Neovascularization

Abstract: Macrophage depletion using CL(2)MDP-lip reduces size, cellularity, and vascularity of CNV. This observation supports the hypothesis that macrophages contribute to the severity of CNV lesions.

Cited by 357 publications

References 33 publications

An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation

An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation

A common haplotype in the complement regulatory gene factor H ( HF1/CFH ) predisposes individuals to age-related macular degeneration

The stereotypical molecular cascade in neovascular age-related macular degeneration: the role of dynamic reciprocity

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