Macrophage Activation Associated with Chronic Murine Cytomegalovirus Infection Results in More Severe Experimental Choroidal Neovascularization

Duke University Eye Center, Duke Center for Macular Diseases, Department of Ophthalmology, Duke University, Durham, North Carolina, United States of America.
PLoS Pathogens (Impact Factor: 7.56). 04/2012; 8(4):e1002671. DOI: 10.1371/journal.ppat.1002671
Source: PubMed


The neovascular (wet) form of age-related macular degeneration (AMD) leads to vision loss due to choroidal neovascularization (CNV). Since macrophages are important in CNV development, and cytomegalovirus (CMV)-specific IgG serum titers in patients with wet AMD are elevated, we hypothesized that chronic CMV infection contributes to wet AMD, possibly by pro-angiogenic macrophage activation. This hypothesis was tested using an established mouse model of experimental CNV. At 6 days, 6 weeks, or 12 weeks after infection with murine CMV (MCMV), laser-induced CNV was performed, and CNV severity was determined 4 weeks later by analysis of choroidal flatmounts. Although all MCMV-infected mice exhibited more severe CNV when compared with control mice, the most severe CNV developed in mice with chronic infection, a time when MCMV-specific gene sequences could not be detected within choroidal tissues. Splenic macrophages collected from mice with chronic MCMV infection, however, expressed significantly greater levels of TNF-α, COX-2, MMP-9, and, most significantly, VEGF transcripts by quantitative RT-PCR assay when compared to splenic macrophages from control mice. Direct MCMV infection of monolayers of IC-21 mouse macrophages confirmed significant stimulation of VEGF mRNA and VEGF protein as determined by quantitative RT-PCR assay, ELISA, and immunostaining. Stimulation of VEGF production in vivo and in vitro was sensitive to the antiviral ganciclovir. These studies suggest that chronic CMV infection may serve as a heretofore unrecognized risk factor in the pathogenesis of wet AMD. One mechanism by which chronic CMV infection might promote increased CNV severity is via stimulation of macrophages to make pro-angiogenic factors (VEGF), an outcome that requires active virus replication.

Download full-text


Available from: Richard D Dix, Jan 21, 2014
  • Source
    • "Depending on the different microenvironment, macrophages can polarize into specific phenotypes, such as M1 or M2 macrophages [17]. The M2 subtype is predominantly pro-angiogenic, facilitating tissue repair and tends to increase during the normal aging process [18]. In contrast, the M1 subtype is predominantly proinflammatory and there is a pathological shift towards M1 subtype with the development of AMD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Age-related macular degeneration (AMD) is a neurodegenerative disease characterized by retinal cell atrophy, and/or choroidal neovascularization in the macula and constitutes the most common cause of blindness among the elderly in industrialized countries. The management of AMD is constrained by our insufficient knowledge of its underlying mechanisms. Recent studies point towards an emerging involvement of interferon-gamma (IFN-γ), a soluble cytokine associated with innate and adaptive immunity. IFN-γ promotes proinflammatory responses by activating proinflammatory cytokines and chemokines, thereby recruiting immune cells such as macrophages and T cells. On the other hand, IFN-γ modulates inflammatory response by upregulating anti-inflammatory factors or inhibiting development of immune cells related to autoimmune response. The complex role of IFN-γ in AMD pathogenesis is intriguing and worth further investigation in terms of therapeutic development.
    02/2013; Suppl 2:0071-76. DOI:10.4172/2155-9570-S2-007
  • [Show abstract] [Hide abstract]
    ABSTRACT: Retinal and choroidal vascular diseases constitute the most common causes of moderate and severe vision loss in developed countries. They can be divided into retinal vascular diseases, in which there is leakage and/or neovascularization (NV) from retinal vessels, and subretinal NV, in which new vessels grow into the normally avascular outer retina and subretinal space. The first category of diseases includes diabetic retinopathy, retinal vein occlusions, and retinopathy of prematurity, and the second category includes neovascular age-related macular degeneration (AMD), ocular histoplasmosis, pathologic myopia, and other related diseases. Retinal hypoxia is a key feature of the first category of diseases resulting in elevated levels of hypoxia-inducible factor-1 (HIF-1) which stimulates expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor-B (PDGF-B), placental growth factor, stromal-derived growth factor-1 and their receptors, as well as other hypoxia-regulated gene products such as angiopoietin-2. Although hypoxia has not been demonstrated as part of the second category of diseases, HIF-1 is elevated and thus the same group of hypoxia-regulated gene products plays a role. Clinical trials have shown that VEGF antagonists provide major benefits for patients with subretinal NV due to AMD and even greater benefits are seen by combining antagonists of VEGF and PDGF-B. It is likely that addition of antagonists of other agents listed above will be tested in the future. Other appealing strategies are to directly target HIF-1 or to use gene transfer to express endogenous or engineered anti-angiogenic proteins. While substantial progress has been made, the future looks even brighter for patients with retinal and choroidal vascular diseases.
    Journal of Molecular Medicine 01/2008; 91(3). DOI:10.1007/s00109-013-0993-5 · 5.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: White blood cells, particularly monocytes and their descendants, macrophages, have been implicated in age-related macular degeneration (AMD) pathology. In this minireview, we describe the current knowledge of monocyte and macrophage involvement in AMD. Chemokine receptors present on these cells such as CCR1, CCR2, and CX3CR1, and their roles in monocyte/macrophage recruitment to sites of injury and inflammation in the context of AMD will be reviewed. Mice models for perturbation of chemokine receptors that recapitulate some of the features of AMD are also described. The body of evidence from human and rodent studies at this point in time suggests that monocyte and macrophages may modulate the course of AMD.
    Advances in Experimental Medicine and Biology 03/2014; 801:199-205. DOI:10.1007/978-1-4614-3209-8_26 · 1.96 Impact Factor
Show more