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      Interleukin-10 Promotes Pathological Angiogenesis by Regulating Macrophage Response to Hypoxia during Development

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          Abstract

          Aberrant angiogenesis in the eye is the most common cause of blindness. The current study examined the role of interleukin-10 (IL-10) in ischemia-induced pathological angiogenesis called neovascularization during postnatal development. IL-10 deficiency resulted in significantly reduced pathological retinal angiogenesis. In contrast to the choroicapillaris where IL-10 interferes with macrophage influx, IL-10 did not prevent anti-angiogenic macrophages from migrating to the retina in response to hypoxia. Instead, IL-10 promoted retinal angiogenesis by altering macrophage angiogenic function, as macrophages from wild-type mice demonstrated increased vascular endothelial growth factor (VEGF) and nitric oxide (NO) compared to IL-10 deficient macrophages. IL-10 appears to directly affect macrophage responsiveness to hypoxia, as macrophages responded to hypoxia with increased levels of IL-10 and STAT3 phosphorylation as opposed to IL-10 deficient macrophages. Also, IL-10 deficient macrophages inhibited the proliferation of vascular endothelial cells in response to hypoxia while wild-type macrophages failed to do so. These findings suggest that hypoxia guides macrophage behavior to a pro-angiogenic phenotype via IL-10 activated pathways.

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          Most cited references30

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          Nitric oxide and macrophage function.

          At the interface between the innate and adaptive immune systems lies the high-output isoform of nitric oxide synthase (NOS2 or iNOS). This remarkable molecular machine requires at least 17 binding reactions to assemble a functional dimer. Sustained catalysis results from the ability of NOS2 to attach calmodulin without dependence on elevated Ca2+. Expression of NOS2 in macrophages is controlled by cytokines and microbial products, primarily by transcriptional induction. NOS2 has been documented in macrophages from human, horse, cow, goat, sheep, rat, mouse, and chicken. Human NOS2 is most readily observed in monocytes or macrophages from patients with infectious or inflammatory diseases. Sustained production of NO endows macrophages with cytostatic or cytotoxic activity against viruses, bacteria, fungi, protozoa, helminths, and tumor cells. The antimicrobial and cytotoxic actions of NO are enhanced by other macrophage products such as acid, glutathione, cysteine, hydrogen peroxide, or superoxide. Although the high-output NO pathway probably evolved to protect the host from infection, suppressive effects on lymphocyte proliferation and damage to other normal host cells confer upon NOS2 the same protective/destructive duality inherent in every other major component of the immune response.
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            Oxygen-induced retinopathy in the mouse.

            To develop oxygen-induced retinopathy in the mouse with reproducible and quantifiable proliferative retinal neovascularization suitable for examining pathogenesis and therapeutic intervention for retinal neovascularization in retinopathy of prematurity (ROP) and other vasculopathologies. One-week-old C57BL/6J mice were exposed to 75% oxygen for 5 days and then to room air. A novel fluorescein-dextran perfusion method has been developed to assess the vascular pattern. The proliferative neovascular response was quantified by counting the nuclei of new vessels extending from the retina into the vitreous in 6 microns sagittal cross-sections. Cross-sections were also stained for glial fibrillary acidic protein (GFAP). Fluorescein-dextran angiography delineated the entire vascular pattern, including neovascular tufts in flat-mounted retinas. Hyperoxia-induced neovascularization occurred at the junction between the vascularized and avascular retina in the mid-periphery. Retinal neovascularization occurred in all the pups between postnatal day 17 and postnatal day 21. There was a mean of 89 neovascular nuclei per cross-section of 9 eyes in hyperoxia compared to less than 1 nucleus per cross-section of 8 eyes in the normoxia control (P < 0.0001). Proliferative vessels were not associated with GFAP-positive astrocyte processes. The authors have described a reproducible and quantifiable mouse model of oxygen-induced retinal neovascularization that should prove useful for the study of pathogenesis of retinal neovascularization as well as for the study of medical intervention for ROP and other retinal angiopathies.
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              Macrophage receptors and immune recognition.

              Macrophages express a broad range of plasma membrane receptors that mediate their interactions with natural and altered-self components of the host as well as a range of microorganisms. Recognition is followed by surface changes, uptake, signaling, and altered gene expression, contributing to homeostasis, host defense, innate effector mechanisms, and the induction of acquired immunity. This review covers recent studies of selected families of structurally defined molecules, studies that have improved understanding of ligand discrimination in the absence of opsonins and differential responses by macrophages and related myeloid cells.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2008
                13 October 2008
                : 3
                : 10
                : e3381
                Affiliations
                [1 ]Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [2 ]Developmental Biology Program, Washington University School of Medicine, St. Louis, Missouri, United States of America
                Instituto Oswaldo Cruz and FIOCRUZ, Brazil
                Author notes

                Conceived and designed the experiments: DSD RSA. Performed the experiments: DSD AAK JK. Analyzed the data: DSD AAK JK RSA. Wrote the paper: DSD JK RSA.

                Article
                08-PONE-RA-05125R1
                10.1371/journal.pone.0003381
                2557127
                18852882
                538babd2-10c6-4c3d-98a5-cca312fb1185
                Dace et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 17 June 2008
                : 17 September 2008
                Page count
                Pages: 10
                Categories
                Research Article
                Cell Biology/Leukocyte Signaling and Gene Expression
                Immunology/Innate Immunity
                Immunology/Leukocyte Activation
                Immunology/Leukocyte Signaling and Gene Expression
                Cardiovascular Disorders/Vascular Biology
                Ophthalmology/Pediatric Ophthalmology
                Ophthalmology/Retinal Disorders

                Uncategorized
                Uncategorized

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