Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death

Kataoka, Keiko; Matsumoto, Hidetaka; Kaneko, Hiroki; Notomi, Shoji; Takeuchi, K.; Sweigard, J. Harry; Atik, Alp; Murakami, Yusuke; Connor, Kip M.; Terasaki, Hiroko; Miller, Joan W.; Vavvas, Demetrios G.

doi:10.1038/cddis.2015.73

Cited by 59 publications

(109 citation statements)

References 64 publications

(88 reference statements)

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“…ORFs are common findings in macula-off detachments, as shown by histology reports [32, 3] and OCT studies [12, 22, 34]. These outer retinal undulations might be secondary to intraretinal proliferation of nonneural cell types occurring within hours of the detachment [30, 31] and might also play a role in the formation of postoperative ORFs [12] (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, the cone loss secondary to RD may result not only in a visual acuity decrease [40], but also in distorted vision. Interestingly, the few patients with macula-on RD who developed metamorphopsia after surgery displayed a hyporeflective outer retina on SD-OCT imaging, suggesting a photoreceptor impairment by mechanisms other than the mechanical disruption of the outer segments such as the inflammation triggered by RD [32, 33, 41]. …”

Section: Discussionmentioning

confidence: 99%

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Impact of Metamorphopsia on Quality of Life after Successful Retinal Detachment Surgery

Saleh¹,

Gauthier²,

Delbosc³

et al. 2018

Ophthalmologica

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Purpose: To determine the impact of metamorphopsia on quality of life after successful retinal detachment (RD) surgery and to determine which retinal changes are related to the most severe distortions. Design: This was a prospective, observational, consecutive study. Methods: The study included 58 eyes of 58 consecutive patients who underwent successful RD surgery. At 6 months postoperatively, the incidence and severity of metamorphopsia were assessed by a quality-of-life questionnaire. Microstructure retinal changes were studied with spectral domain optical coherence tomography (OCT). The questionnaire score was compared with pre- and postoperative OCT findings. Results: Overall, 20 patients (34.5%) had metamorphopsia. Outer retinal folds (ORFs) and the macular status before surgery, together with postoperative ORFs and decrease in ellipsoid and/or interdigitation photoreceptor zone reflectivity, were identified as risk factors of developing metamorphopsia (relative risk, 1.7–4.8). The most severe visual distortions were associated with ORFs. Conclusion: Metamorphopsia is a frequent occurrence after RD surgery and its impact on patients’ quality of life appears to be limited. While it may be difficult to prevent photoreceptor loss occurring after surgery, limiting postoperative ORFs may be helpful in reducing their incidence.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impact of Metamorphopsia on Quality of Life after Successful Retinal Detachment Surgery

Saleh¹,

Gauthier²,

Delbosc³

et al. 2018

Ophthalmologica

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“…Several studies have also indicated that IL-1β is secreted by microglia in photo-oxidative damage [22, 23], as well as in models of neovascular AMD [24], retinitis pigmentosa [25], and retinal detachment [26]. In this study, we tested the hypothesis that IL-1β promotes the up-regulation of chemokines in Müller cells and RPE, increasing outer-retinal macrophage accumulation and photoreceptor death, using a model of focal retinal degeneration.…”

Section: Introductionmentioning

confidence: 99%

Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration

Natoli

Fernando

Madigan

et al. 2017

Mol Neurodegeneration

104

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BackgroundChemokine signalling is required for the homing of leukocytes during retinal inflammation, and is associated with pathogenesis of diseases such as age-related macular degeneration (AMD). Here, we explore the role of interleukin-1β (IL-1β) in modulating AMD-associated chemokines Ccl2, Cxcl1, and Cxcl10 during photo-oxidative retinal damage, and the effect on both the accumulation of outer-retinal macrophages, and death of photoreceptors.MethodsInhibition of retinal IL-1β expression was performed using either siRNA or antibody neutralisation, which was intravitreally injected in SD rats prior to photo-oxidative damage. Changes in the expression and localisation of Il-1β, Ccl2, Cxcl1 and Cxcl10 genes were assessed using qPCR and in situ hybridisation, while the recruitment of retinal macrophages was detected using immunohistochemistry for IBA1. Levels of photoreceptor cell death were determined using TUNEL.ResultsPhoto-oxidative damage elevated the expression of Il-1β and inflammasome-related genes, and IL-1β protein was detected in microglia infiltrating the outer retina. This was associated with increased expression of Ccl2, Cxcl1, and Cxcl10. Intravitreal IL-1β inhibitors suppressed chemokine expression following damage and reduced macrophage accumulation and photoreceptor death. Moreover, in Müller and RPE cell cultures, and in vivo, Ccl2, Cxcl1 and Cxcl10 were variously upregulated when stimulated with IL-1β, with increased macrophage accumulation detected in vivo.ConclusionsIL-1β is produced by retinal microglia and macrophages and promotes chemokine expression by Müller cells and RPE in retinal degeneration. Targeting IL-1β may prove efficacious in broadly suppressing chemokine-mediated inflammation in retinal dystrophies such as AMD.

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“…In patients with photoreceptor injury associated with retinal detachment, we found increased levels of cleaved interleukin 1 beta (IL1β), a downstream product of inflammasome activation. 31 In rodents with experimental retinal detachment, infiltrating macrophages were the primary source of IL1β, and photoreceptor cell death led to inflammasome activation in a macrophage- and RIP3-dependent manner. 31 Additionally, we found that resident microglia and infiltrating macrophages express FasL, which triggered photoreceptor death in the membrane-bound form (mFasL) yet had neuroprotective properties in the soluble form (sFasL).…”

Section: Neuroprotectionmentioning

confidence: 99%

“…31 In rodents with experimental retinal detachment, infiltrating macrophages were the primary source of IL1β, and photoreceptor cell death led to inflammasome activation in a macrophage- and RIP3-dependent manner. 31 Additionally, we found that resident microglia and infiltrating macrophages express FasL, which triggered photoreceptor death in the membrane-bound form (mFasL) yet had neuroprotective properties in the soluble form (sFasL). 32 We thus believe that neuroprotection may provide a broad-based treatment approach for a wide variety of retinal disorders, including AMD.…”

Section: Neuroprotectionmentioning

confidence: 99%

Beyond VEGF—The Weisenfeld Lecture

Miller¹

2016

Invest. Ophthalmol. Vis. Sci.

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PurposeTo review advances made in the treatment of age-related macular degeneration (AMD) and share perspectives on the future of AMD treatment.MethodsReview of published clinical and experimental studies.ResultsInhibitors of vascular endothelial growth factor (VEGF) truly revolutionized the treatment of AMD. However, available results from longer-term studies suggest that a degenerative process is unveiled, and continues to occur, even when neovascularization is controlled. Furthermore, anti-VEGF therapy may play a role in the development of atrophic changes. We have proposed using neuroprotection to prevent atrophy, and multiple models of retinal degeneration have shown that it is necessary to block both apoptotic and necrotic cell death pathways. Despite the success of anti-VEGF therapy and the promise of neuroprotection, neither addresses the underlying cause of AMD. It has been postulated that in early AMD, the retention and abnormal accumulation of lipids in Bruch's membrane and below the retinal pigmented epithelium (RPE) lead to drusen. Thus, it is conceivable to target the retained lipoproteins and seek to remove them. In a case study and pilot multicenter clinical trial, we observed significant regression of drusen and an improvement in visual acuity in patients taking high-dose statin therapy. These results, though preliminary, warrant further investigation.ConclusionFuture treatment of AMD should be based on biology, which will require continued elucidation of the pathogenic mechanisms of AMD development. Neuroprotection represents a potential therapeutic approach, and other promising targets include immune pathways (e.g., inflammation, complement, and inflammasomes) and lipid/lipoprotein accumulation. Finally, due to the heterogeneity of AMD, future progress in therapy will benefit from improved phenotyping and classification.

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Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death

Cited by 59 publications

References 64 publications

Impact of Metamorphopsia on Quality of Life after Successful Retinal Detachment Surgery

Impact of Metamorphopsia on Quality of Life after Successful Retinal Detachment Surgery

Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration

Beyond VEGF—The Weisenfeld Lecture

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