The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes
The dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies, where ocular hypertension (OHT) is the major risk factor. We investigated the impact of transient non-ischemic OHT spikes (spOHT) on RGC function and viability in v...
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MDPI AG
2023-11-01
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author | Markus Spurlock Weijun An Galina Reshetnikova Rong Wen Hua Wang Michelle Braha Gabriela Solis Stefan Kurtenbach Orlando J. Galindez Juan Pablo de Rivero Vaccari Tsung-Han Chou Vittorio Porciatti Valery I. Shestopalov |
author_facet | Markus Spurlock Weijun An Galina Reshetnikova Rong Wen Hua Wang Michelle Braha Gabriela Solis Stefan Kurtenbach Orlando J. Galindez Juan Pablo de Rivero Vaccari Tsung-Han Chou Vittorio Porciatti Valery I. Shestopalov |
author_sort | Markus Spurlock |
collection | DOAJ |
description | The dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies, where ocular hypertension (OHT) is the major risk factor. We investigated the impact of transient non-ischemic OHT spikes (spOHT) on RGC function and viability in vivo to identify cellular pathways linking low-grade repetitive mechanical stress to RGC pathology. We found that repetitive spOHT had an unexpectedly high impact on intraocular homeostasis and RGC viability, while exposure to steady OHT (stOHT) of a similar intensity and duration failed to induce pathology. The repetitive spOHT induced the rapid activation of the inflammasome, marked by the upregulation of NLRP1, NLRP3, AIM2, caspases -1, -3/7, -8, and Gasdermin D (GSDMD), and the release of interleukin-1β (IL-1β) and other cytokines into the vitreous. Similar effects were also detected after 5 weeks of exposure to chronic OHT in an induced glaucoma model. The onset of these immune responses in both spOHT and glaucoma models preceded a 50% deficit in pattern electroretinogram (PERG) amplitude and a significant loss of RGCs 7 days post-injury. The inactivation of inflammasome complexes in <i>Nlrp1</i><sup>−/−</sup>, <i>Casp1</i><sup>−/−</sup>, and <i>GsdmD</i><sup>−/−</sup> knockout animals significantly suppressed the spOHT-induced inflammatory response and protected RGCs. Our results demonstrate that mechanical stress produced by acute repetitive spOHT or chronic OHT is mechanistically linked to inflammasome activation, which leads to RGC dysfunction and death. |
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language | English |
last_indexed | 2024-03-09T16:56:02Z |
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spelling | doaj.art-b7c16fccb0604e06baa7cbb92d4a88e02023-11-24T14:35:22ZengMDPI AGCells2073-44092023-11-011222262610.3390/cells12222626The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure SpikesMarkus Spurlock0Weijun An1Galina Reshetnikova2Rong Wen3Hua Wang4Michelle Braha5Gabriela Solis6Stefan Kurtenbach7Orlando J. Galindez8Juan Pablo de Rivero Vaccari9Tsung-Han Chou10Vittorio Porciatti11Valery I. Shestopalov12Bascom Palmer Eye Institute Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USABascom Palmer Eye Institute Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USABascom Palmer Eye Institute Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USABascom Palmer Eye Institute Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USABascom Palmer Eye Institute Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USABascom Palmer Eye Institute Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USABascom Palmer Eye Institute Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USABascom Palmer Eye Institute Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USADepartment of Neurological Surgery and The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USANeuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USABascom Palmer Eye Institute Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USABascom Palmer Eye Institute Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USABascom Palmer Eye Institute Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USAThe dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies, where ocular hypertension (OHT) is the major risk factor. We investigated the impact of transient non-ischemic OHT spikes (spOHT) on RGC function and viability in vivo to identify cellular pathways linking low-grade repetitive mechanical stress to RGC pathology. We found that repetitive spOHT had an unexpectedly high impact on intraocular homeostasis and RGC viability, while exposure to steady OHT (stOHT) of a similar intensity and duration failed to induce pathology. The repetitive spOHT induced the rapid activation of the inflammasome, marked by the upregulation of NLRP1, NLRP3, AIM2, caspases -1, -3/7, -8, and Gasdermin D (GSDMD), and the release of interleukin-1β (IL-1β) and other cytokines into the vitreous. Similar effects were also detected after 5 weeks of exposure to chronic OHT in an induced glaucoma model. The onset of these immune responses in both spOHT and glaucoma models preceded a 50% deficit in pattern electroretinogram (PERG) amplitude and a significant loss of RGCs 7 days post-injury. The inactivation of inflammasome complexes in <i>Nlrp1</i><sup>−/−</sup>, <i>Casp1</i><sup>−/−</sup>, and <i>GsdmD</i><sup>−/−</sup> knockout animals significantly suppressed the spOHT-induced inflammatory response and protected RGCs. Our results demonstrate that mechanical stress produced by acute repetitive spOHT or chronic OHT is mechanistically linked to inflammasome activation, which leads to RGC dysfunction and death.https://www.mdpi.com/2073-4409/12/22/2626ocular hypertensionintraocular pressure spikesretinal ganglion cellsinflammasomecaspase-1interleukin-1β |
spellingShingle | Markus Spurlock Weijun An Galina Reshetnikova Rong Wen Hua Wang Michelle Braha Gabriela Solis Stefan Kurtenbach Orlando J. Galindez Juan Pablo de Rivero Vaccari Tsung-Han Chou Vittorio Porciatti Valery I. Shestopalov The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes Cells ocular hypertension intraocular pressure spikes retinal ganglion cells inflammasome caspase-1 interleukin-1β |
title | The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes |
title_full | The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes |
title_fullStr | The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes |
title_full_unstemmed | The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes |
title_short | The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes |
title_sort | inflammasome dependent dysfunction and death of retinal ganglion cells after repetitive intraocular pressure spikes |
topic | ocular hypertension intraocular pressure spikes retinal ganglion cells inflammasome caspase-1 interleukin-1β |
url | https://www.mdpi.com/2073-4409/12/22/2626 |
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