Spurlock, M.; An, W.; Reshetnikova, G.; Wen, R.; Wang, H.; Braha, M.; Solis, G.; Kurtenbach, S.; Galindez, O.J.; de Rivero Vaccari, J.P.; Chou, T.-H.; Porciatti, V.; Shestopalov, V.I. The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes. Cells2023, 12, 2626.
Spurlock, M.; An, W.; Reshetnikova, G.; Wen, R.; Wang, H.; Braha, M.; Solis, G.; Kurtenbach, S.; Galindez, O.J.; de Rivero Vaccari, J.P.; Chou, T.-H.; Porciatti, V.; Shestopalov, V.I. The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes. Cells 2023, 12, 2626.
Spurlock, M.; An, W.; Reshetnikova, G.; Wen, R.; Wang, H.; Braha, M.; Solis, G.; Kurtenbach, S.; Galindez, O.J.; de Rivero Vaccari, J.P.; Chou, T.-H.; Porciatti, V.; Shestopalov, V.I. The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes. Cells2023, 12, 2626.
Spurlock, M.; An, W.; Reshetnikova, G.; Wen, R.; Wang, H.; Braha, M.; Solis, G.; Kurtenbach, S.; Galindez, O.J.; de Rivero Vaccari, J.P.; Chou, T.-H.; Porciatti, V.; Shestopalov, V.I. The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes. Cells 2023, 12, 2626.
Abstract
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 similar intensity and duration failed to induce pathology. The repetitive spOHT induced a rapid activation of the inflammasome, marked by the upregulation of NLRP1, NLRP3, AIM2, caspases -1, -3/7, -8, 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 electroretinograms (PERG) amplitude, and significant loss of RGCs at 7 days post-injury. Inactivation of inflammasome complexes in NLRP1-/- , Casp1-/- and GsdmD-/- 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.
Biology and Life Sciences, Neuroscience and Neurology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
,
