Microglia in the Mouse Retina Alter the Structure and Function of Retinal Pigmented Epithelial Cells: A Potential Cellular Interaction Relevant to AMD

Ma, Wenxin; Zhao, Lian; Fontainhas, Aurora M.; Fariss, Robert N.; Wong, Wai T.

doi:10.1371/journal.pone.0007945

Cited by 182 publications

(156 citation statements)

References 57 publications

(58 reference statements)

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“…The latter can be perturbed through the augmentation of inhibitory CD200R signalling or through the administration of Th2 cytokines to either tonically suppress macrophage activation or drive anti-angiogenic function, respectively. 94,96,98 Thus our data and those from others 99,100 support the concept that interplay between macrophage and RPE within the subretinal space likely contributes to disease progression.…”

Section: Macrophage Conditioning Angiogenesis and Tissue Viabilitysupporting

confidence: 86%

Doyne lecture 2016: intraocular health and the many faces of inflammation

Dick

2016

Eye

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Dogma for reasons of immune privilege including sequestration (sic) of ocular antigen, lack of lymphatic and immune competent cells in the vital tissues of the eye has long evaporated. Maintaining tissue and cellular health to preserve vision requires active immune responses to prevent damage and respond to danger. A priori the eye must contain immune competent cells, undergo immune surveillance to ensure homoeostasis as well as an ability to promote inflammation. By interrogating immune responses in non-infectious uveitis and compare with age-related macular degeneration (AMD), new concepts of intraocular immune health emerge. The role of macrophage polarisation in the two disorders is a tractable start. TNF-alpha regulation of macrophage responses in uveitis has a pivotal role, supported via experimental evidence and validated by recent trial data. Contrast this with the slow, insidious degeneration in atrophic AMD or in neovasular AMD, with the compelling genetic association with innate immunity and complement, highlights an ability to attenuate pathogenic immune responses and despite known inflammasome activation. Yolk sac-derived microglia maintains tissue immune health. The result of immune cell activation is environmentally dependent, for example, on retinal cell bioenergetics status, autophagy and oxidative stress, and alterations that skew interaction between macrophages and retinal pigment epithelium (RPE). For example, dead RPE eliciting macrophage VEGF secretion but exogenous IL-4 liberates an anti-angiogenic macrophage sFLT-1 response. Impaired autophagy or oxidative stress drives inflammasome activation, increases cytotoxicity, and accentuation of neovascular responses, yet exogenous inflammasome-derived cytokines, such as IL-18 and IL-33, attenuate responses.

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Section: Macrophage Conditioning Angiogenesis and Tissue Viabilitysupporting

confidence: 86%

Doyne lecture 2016: intraocular health and the many faces of inflammation

Dick

2016

Eye

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“…Two characteristic features of low grade retinal chronic inflammation are complement deposition at Bruch's membrane and an increased number of subretinal microglia/ macrophages (43). Although studies suggest a beneficial effect of these subretinal immune cells in tissue homeostasis (43)(44)(45), detrimental roles of activated microglial cells have been documented in AMD patients (46) and various disease models (47,48). In this study, invasion of microglia into the subretinal space was documented in mice with retinal degeneration caused by Mertk deficiency.…”

Section: Journal Of Biological Chemistry 26943mentioning

confidence: 76%

Receptor MER Tyrosine Kinase Proto-oncogene (MERTK) Is Not Required for Transfer of Bis-retinoids to the Retinal Pigmented Epithelium

Palczewska

Maeda

Golczak

et al. 2016

Journal of Biological Chemistry

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Edited by George CarmanAccumulation of bis-retinoids in the retinal pigmented epithelium (RPE) is a hallmark of aging and retinal disorders such as Stargardt disease and age-related macular degeneration. These aberrant fluorescent condensation products, including di-retinoid-pyridinium-ethanolamine (A2E), are thought to be transferred to RPE cells primarily through phagocytosis of the photoreceptor outer segments. However, we observed by twophoton microscopy that mouse retinas incapable of phagocytosis due to a deficiency of the c-Mer proto-oncogene tyrosine kinase (Mertk) nonetheless contained fluorescent retinoid condensation material in their RPE. Primary RPE cells from Mertk ؊/؊ mice also accumulated fluorescent products in vitro.Finally, quantification of A2E demonstrated the acquisition of retinal condensation products in Mertk ؊/؊ mouse RPE prior to retinal degeneration. In these mice, we identified activated microglial cells that likely were recruited to transport A2E-like condensation products to the RPE and dispose of the dying photoreceptor cells. These observations demonstrate a novel transport mechanism between photoreceptor cells and RPE that does not involve canonical Mertk-dependent phagocytosis.Maintaining the health of the vertebrate retina requires a delicate interaction between retinal photoreceptor cells, which collect and transmit visual stimuli, and the adjacent retinal pigmented epithelium (RPE), 4 a cell layer that forms part of the blood-retina barrier (1). Disturbances in this interaction, whether through genetic defects, environmental insults, or trauma can lead to retinal degeneration and ultimate loss of vision (2, 3). The RPE performs many vital functions, including the daily removal of the older distal portions of photoreceptor outer segments (4 -6) and the delivery of both nutrients and the 11-cis-retinal chromophore to rod and cone photoreceptor cells that sustain vision (7). Roughly 10% of each photoreceptor cell outer segment is shed daily throughout an animal's life, distinguishing the RPE as perhaps the most active phagocytic cell layer in the body (5). Although RPE phagocytosis was discovered over 40 years ago (4), the molecular mechanisms underlying this process have not been delineated. However, certain molecular components that support classic phagocytosis have been identified, including the tyrosine receptor kinase Mertk (8, 9). The RPE not only removes toxic photo-oxidation products that accumulate in the retina, but it also recycles usable materials such as proteins, lipids, and small molecules. Retinoid condensation products such as bis-retinoids (di-retinoidpyridinium-ethanolamine (A2E), retinoid dimers, and others) generated in photoreceptors are presumably transported along with photoreceptor membranes to the RPE during phagocytosis. Highly fluorescent A2E accumulation is a pathogenic hallmark of Stargardt disease, the most common juvenile form of human macular degeneration (10). A2E accumulation also is thought to contribute to the pathogenesis of age-related mac...

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“…Recent studies suggest a pathogenic role for subretinal macrophages (42,59), even though they contribute to the clearance of photoreceptor cell debris. In this work, subretinal microglia/macrophages elicited an AF signal with a similar spectrum in both ROS and RPE cells, also suggesting subretinal microglia/macrophage involvement in clearing of ROS debris.…”

Section: Discussionmentioning

confidence: 99%

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

Maeda

Palczewska

Golczak³

et al. 2014

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

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Atrophic age-related and juvenile macular degeneration are especially devastating due to lack of an effective cure. Two retinal cell types, photoreceptor cells and the adjacent retinal pigmented epithelium (RPE), reportedly display the earliest pathological changes. Abca4 −/− Rdh8 −/− mice, which mimic many features of human retinal degeneration, allowed us to determine the sequence of light-induced events leading to retinal degeneration. Using two-photon microscopy with 3D reconstruction methodology, we observed an initial strong retinoid-derived fluorescence and expansion of Abca4 −/− Rdh8 −/− mouse rod cell outer segments accompanied by macrophage infiltration after brief exposure of the retina to bright light. Additionally, light-dependent fluorescent compounds produced in rod outer segments were not transferred to the RPE of mice genetically defective in RPE phagocytosis. Collectively, these findings suggest that for light-induced retinopathies in mice, rod photoreceptors are the primary site of toxic retinoid accumulation and degeneration, followed by secondary changes in the RPE.

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Microglia in the Mouse Retina Alter the Structure and Function of Retinal Pigmented Epithelial Cells: A Potential Cellular Interaction Relevant to AMD

Cited by 182 publications

References 57 publications

Doyne lecture 2016: intraocular health and the many faces of inflammation

Doyne lecture 2016: intraocular health and the many faces of inflammation

Receptor MER Tyrosine Kinase Proto-oncogene (MERTK) Is Not Required for Transfer of Bis-retinoids to the Retinal Pigmented Epithelium

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

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