Photoreceptor Proteins Initiate Microglial Activation via Toll-like Receptor 4 in Retinal Degeneration Mediated by All-trans-retinal

Kohno, Hideo; Chen, Yu; Kevany, Brian M.; Pearlman, Eric; Miyagi, Masaru; Maeda, Tadao; Palczewski, Krzysztof; Maeda, Akiko

doi:10.1074/jbc.m112.448712

Cited by 155 publications

(199 citation statements)

References 89 publications

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“…Moreover, the RPE of these mice failed to display any AF changes, clearly indicating that A2E is not the primary initiator of light-induced retinal degeneration in this mouse model. However, Mertk-deficient mice did reveal infiltration of microglia/macrophages into the subretinal space (42,52), indicating that these cells likely contribute to the clearance of photoreceptor cell debris.…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…WT, 5′-CTTCAAAGTCAGTGGTGACTGGG-3′ and 5′-GCTATCCAGCTGCGACA-ATTC-3′; and Rdh8 mutant, 5′-TCCGCCTTGGAAACCTGAGCCAGAAG-3′ and 5′-TGCGAGGCCAGAGGCCACTTGTGTAGC-3′ (12,32,42). Mertk −/− and Cx3cr1 gfp/Δ mice were purchased from The Jackson Laboratory.…”

Section: Methodsmentioning

confidence: 99%

“…1A could represent infiltrating microglia/macrophages (40,41). Translocation of microglia/macrophages into the subretinal space is one of the features of retinal inflammation found in degenerating retinas (42,43). A second concern was that even though retinal infiltrating cells had been imaged by SLO as AF granules in Abca4 −/− Rdh8 −/− mice after light illumination (41,42), neither their fluorescence spectra nor their z location within the retina were known.…”

Section: Tpm Noninvasively Images Autofluorescence (Af) Signals Frommentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Tpm Noninvasively Images Autofluorescence (Af) Signals Frommentioning

confidence: 99%

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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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“…1 safe light filter (transmittance Ͼ560 nm). (34). qRT-PCR was performed with the following primers: mouse Gapdh, forward (5Ј-GTGTTCCTACCCCCAATGTG-3Ј), reverse (5Ј-AGGA-GACAACCTGGTCCTCA-3Ј); mouse Atg7 forward (5Ј-ACC-ATGCAGGGAGCTAGAGA-3Ј) and reverse (5Ј-CCACTGA-GGTTCACCATCCT-3Ј); mouse CFH, forward (5Ј-TGGACT-TCCTTGTGGACCTC-3Ј), reverse (5Ј-TGGGTCAGACCA-CTTTCCTC-3Ј); human RPE65 forward (5Ј-AAAAATGCCA-GAAAGGCTCC-3Ј) and reverse (5Ј-AGTTGTATTGGGGA-GCGTGA-3Ј); human MERTK forward (5Ј-GAAATTACAG-TCCGCAGCC-3Ј) and reverse (5Ј-TCTTCCCTTGCCTCAG-TGAT-3Ј); human BEST1 forward (5Ј-GCTGCTATATGGC-GAGTTCTT-3Ј) and reverse (5Ј-CAGCTGTTGTTCTTCCG-TGA-3Ј) and human MITF forward (5Ј-CAAATACGTTGCC-TGTCTCGGG-3Ј) and reverse (5Ј-GGGTGGACAGGAGTT-GCTGA-3Ј).…”

Section: Methodsmentioning

confidence: 99%

Di-retinoid-pyridinium-ethanolamine (A2E) Accumulation and the Maintenance of the Visual Cycle Are Independent of Atg7-mediated Autophagy in the Retinal Pigmented Epithelium

Perusek¹,

Sahu²,

Parmar³

et al. 2015

Journal of Biological Chemistry

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Background: Atg7 is an essential autophagic enzyme. Disrupted autophagy has been implicated in retinal degeneration. Results: Mice with RPE-specific Atg7 deletion exhibit normal retinoid recycling, histology, and A2E accumulation, but display hypertrophy and cytosolic debris. Conclusion: Atg7 deficiency does not severely affect the health of RPE cells in mice. Significance: A2E accumulation and retinoid recycling are independent of Atg7-mediated autophagy in RPE cells.

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Replication ofMycobacterium Tuberculosisin Retinal Pigment Epithelium

2014

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uberculosis (TB) remains a global health problem, with almost one-third of the world's population being infected. 1 The disease presents primarily as pulmonary TB and, in approximately 20% of patients, as extrapulmonary disease. After Mycobacterium tuberculosis has been inhaled, the organisms undergo phagocytosis by alveolar macrophages, resulting in bacterial containment. 2 In some patients, the bacilli may disseminate systemically, establishing latent infection at extrapulmonary sites, with the potential to reactivate at a later time. 2 Reactivation of latent TB usually occurs when the host's immune system is compromised. 3,4 Extrapulmonary TB is believed to result from reactivation of latent mycobacteria residing within resident reticuloendothelial cells. Ocular TB is a form of extrapulmonary TB manifesting primarily as posterior uveitis. 5 However, the location of latent TB organisms in the eye is not clear. In a study of TB-related posterior uveitis, Rao et al 6 proposed that M tuberculosis may reside in the retinal pigment epithelium (RPE). However, the mechanisms underlying phagocytosis and growth containment of the bacilli by RPE remain unknown. The normal clinical appearance of RPE in individuals before reactivation of M tuberculosis suggests that latent M tuberculosis infection does not induce necrosis or apoptosis. IMPORTANCE Mycobacterium tuberculosis is an important cause of posterior uveitis in tuberculosis-endemic regions. Clinical and histopathologic evidence suggests that retinal pigment epithelium (RPE) can harbor M tuberculosis. However, the mechanism of M tuberculosis phagocytosis and its growth in RPE is not clear.OBJECTIVE To investigate M tuberculosis phagocytosis, replication, and cytopathic effects in RPE cells compared with macrophages. DESIGN, SETTING, AND PARTICIPANTSHuman fetal RPE and monocytic leukemia macrophage (THP-1) cell lines were cultured, and RPE and THP-1 cells were exposed to avirulent M tuberculosis H37Ra. Mycobacteria were added to RPE and THP-1 cells with a 5:1 multiplicity of infection. Nonphagocytized M tuberculosis was removed after 12 hours of exposure (day 0). Cells were harvested at days 0, 1, and 5 to count live and dead cells and intracellular mycobacteria. Toll-like receptor 2 (TLR2) and TLR4 expression was determined by immunohistochemistry; intracellular bacillary load, following TLR2 and TLR4 blockade. MAIN OUTCOMES AND MEASURES Number of intracellular M tuberculosis, cell survival, and TLR2 and TLR4 expression in RPE and THP-1 cells following exposure to M tuberculosis. RESULTS At day 0, an equal number of intracellular M tuberculosis was observed per THP-1 and RPE cells (0.45 and 0.35 M tuberculosis per RPE and THP-1 cells, respectively). Mean (SD)number of intracellular M tuberculosis at day 5 was 1.9 (0.03) and 3.3 (0.01) per RPE and THP-1 cells, respectively (P < .001). Viability of infected RPE was significantly greater than that of THP-1 cells at day 5 (viable cells: 17 [8%] THP-1 vs 73% [4%] RPE; P < .05). Expression of TLR2 and TLR4 was detected in ...

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Photoreceptor Proteins Initiate Microglial Activation via Toll-like Receptor 4 in Retinal Degeneration Mediated by All-trans-retinal

Cited by 155 publications

References 89 publications

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

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

Di-retinoid-pyridinium-ethanolamine (A2E) Accumulation and the Maintenance of the Visual Cycle Are Independent of Atg7-mediated Autophagy in the Retinal Pigmented Epithelium

Replication ofMycobacterium Tuberculosisin Retinal Pigment Epithelium

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