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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-1\u03b2 (IL-1\u03b2) 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 Nlrp1\u2212\/\u2212, Casp1\u2212\/\u2212, and GsdmD\u2212\/\u2212 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.<\/jats:p>","DOI":"10.3390\/cells12222626","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T00:47:48Z","timestamp":1700009268000},"page":"2626","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes"],"prefix":"10.3390","volume":"12","author":[{"given":"Markus","family":"Spurlock","sequence":"first","affiliation":[{"name":"Bascom Palmer Eye Institute Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, 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J.","family":"Galindez","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery and The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5460-8834","authenticated-orcid":false,"given":"Juan Pablo","family":"de Rivero Vaccari","sequence":"additional","affiliation":[{"name":"Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Department of Neurological Surgery and The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1986-6088","authenticated-orcid":false,"given":"Tsung-Han","family":"Chou","sequence":"additional","affiliation":[{"name":"Bascom Palmer Eye Institute Department of Ophthalmology, University of Miami 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