{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T21:48:30Z","timestamp":1769636910839,"version":"3.49.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T00:00:00Z","timestamp":1718236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>Previous studies have reported Caspase-1 (<jats:italic>Casp1<\/jats:italic>) is upregulated in mouse models of Juvenile X-linked Retinoschisis (XLRS), however no functional role for <jats:italic>Casp1<\/jats:italic> in disease progression has been identified. We performed electroretinogram (ERG) and standardized optical coherence tomography (OCT) in mice deficient in the Retinoschisin-1 (<jats:italic>Rs1<\/jats:italic>) and <jats:italic>Casp1<\/jats:italic> and Caspase-11 <jats:italic>(Casp11)<\/jats:italic> genes (<jats:italic>Rs1<\/jats:italic>-KO<jats:italic>;Casp1\/11<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>) to test the hypothesis that <jats:italic>Casp1<\/jats:italic> may play a role in disease evolution and or severity of disease. Currently, no studies have ventured to investigate the longer-term effects of <jats:italic>Casp1<\/jats:italic> on phenotypic severity and disease progression over time in XLRS, and specifically the effect on electroretinogram.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>Rs1<\/jats:italic>-KO;<jats:italic>Casp1\/11<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice were generated by breeding <jats:italic>Rs1<\/jats:italic>-KO mice with <jats:italic>Casp1\/11<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice. OCT imaging was analyzed at 2-, 4-, and 15\u201316\u2009months of age. Outer nuclear layer (ONL) thickness and adapted standardized cyst severity score were measured and averaged from 4 locations 500\u2009\u03bcm from the optic nerve. Adapted standardized cyst severity score was 1: absent cysts, 2: &amp;lt;30\u2009\u03bcm, 3: 30\u201349\u2009\u03bcm, 4: 50\u201369\u2009\u03bcm, 5: 70\u201399\u2009\u03bcm, 6: &amp;gt;99\u2009\u03bcm. Electroretinograms (ERG) were recorded in dark-adapted and light-adapted conditions at 2 and 4\u2009months. Results obtained from <jats:italic>Rs1<\/jats:italic>-KO and <jats:italic>Rs1<\/jats:italic>-KO;<jats:italic>Casp1\/11<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> eyes were compared with age matched WT control eyes at 2\u2009months.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Intraretinal schisis was not observed on OCT in WT eyes, while schisis was apparent in most <jats:italic>Rs1<\/jats:italic>-KO and <jats:italic>Rs1<\/jats:italic>-KO;<jats:italic>Casp1\/11<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> eyes at 2 and 4\u2009months of age. There was no difference in the cyst severity score from 2 to 4\u2009months of age, or ONL thickness from 2 to 16\u2009months of age between <jats:italic>Rs1<\/jats:italic>-KO and <jats:italic>Rs1<\/jats:italic>-KO;<jats:italic>Casp1\/11<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> eyes. ERG amplitudes were similarly reduced in <jats:italic>Rs1<\/jats:italic>-KO and <jats:italic>Rs1<\/jats:italic>-KO;<jats:italic>Casp1\/11<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> compared to WT controls at 2\u2009months of age, and there was no difference between <jats:italic>Rs1-<\/jats:italic>KO and <jats:italic>Rs1<\/jats:italic>-KO;<jats:italic>Casp1\/11<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> eyes at 2 or 4\u2009months of age, suggesting no impact on the electrical function of photoreceptors over time in the absence of <jats:italic>Casp1<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Although <jats:italic>Casp1<\/jats:italic> has been reported to be significantly upregulated in <jats:italic>Rs1-<\/jats:italic>KO mice, our preliminary data suggest that removing <jats:italic>Casp1\/11<\/jats:italic> does not modulate photoreceptor electrical function or alter the trajectory of the retinal architecture over time.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2024.1347599","type":"journal-article","created":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T04:29:23Z","timestamp":1718252963000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Investigating the role of Caspase-1 in a mouse model of Juvenile X-linked Retinoschisis"],"prefix":"10.3389","volume":"11","author":[{"given":"Ella 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nonhereditary idiopathic foveomacular retinoschisis","volume":"33","author":"Fragiotta","year":"2019","journal-title":"Eye"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"3279","DOI":"10.1167\/iovs.04-0576","article-title":"RS-1 gene delivery to an adult Rs1h knockout mouse model restores ERG b-wave with reversal of the electronegative waveform of X-linked Retinoschisis","volume":"45","author":"Zeng","year":"2004","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2030","DOI":"10.1016\/j.ymthe.2021.02.013","article-title":"Immune function in X-linked retinoschisis subjects in an AAV8-RS1 phase I\/IIa gene therapy trial","volume":"29","author":"Mishra","year":"2021","journal-title":"Mol Ther"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1016\/j.oret.2022.06.013","article-title":"Intravitreal delivery of rAAV2tYF-CB-hRS1 vector for gene augmentation therapy in patients with X-linked Retinoschisis: 1-year clinical results","volume":"6","author":"Pennesi","year":"2022","journal-title":"Ophthalmol Retina"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1159\/000094799","article-title":"The role of caspases in photoreceptor cell death of the retinoschisin-deficient mouse","volume":"115","author":"Gehrig","year":"2006","journal-title":"Cytogenet Genome Res"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/nri.2015.7","article-title":"Converging roles of caspases in inflammasome activation, cell death and innate immunity","volume":"16","author":"Man","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/nature10558","article-title":"Non-canonical inflammasome activation targets 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Ophthalmol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1101\/2023.10.09.561513","article-title":"An osmolarity dependent mechanism partially ameliorates retinal cysts and rescues cone function in a mouse model of X-linked Retinoschisis","volume":"6","author":"Gehrke","year":"2023","journal-title":"bioRxiv"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"5181","DOI":"10.1167\/iovs.06-0556","article-title":"Caspase-1 ablation protects photoreceptors in a model of autosomal dominant retinitis pigmentosa","volume":"47","author":"Samardzija","year":"2006","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/S0006-8993(02)04125-2","article-title":"Light-induced photoreceptor degeneration may involve the NF kappa B\/caspase-1 pathway in vivo","volume":"967","author":"Wu","year":"2003","journal-title":"Brain Res"},{"key":"ref16","first-page":"252","article-title":"Gene expression in the mouse retina: the effect of damaging light","volume":"6","author":"Grimm","year":"2000","journal-title":"Mol Vis"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1111\/jcmm.13019","article-title":"The X-linked juvenile retinoschisis protein retinoschisin is a novel regulator of mitogen-activated protein kinase signalling and apoptosis in the retina","volume":"21","author":"Plossl","year":"2017","journal-title":"J Cell Mol Med"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1186\/s12974-023-02800-2","article-title":"An ocular Th1 immune response promotes corneal nerve damage independently of the development of corneal epitheliopathy","volume":"20","author":"Vereertbrugghen","year":"2023","journal-title":"J Neuroinflammation"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1111\/imr.12289","article-title":"Bacterial recognition pathways that lead to inflammasome activation","volume":"265","author":"Storek","year":"2015","journal-title":"Immunol Rev"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1016\/j.it.2019.09.005","article-title":"Emerging activators and regulators of Inflammasomes and Pyroptosis","volume":"40","author":"Xue","year":"2019","journal-title":"Trends Immunol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1189\/jlb.3MR0516-224R","article-title":"Caspase-1 as a multifunctional inflammatory mediator: noncytokine maturation roles","volume":"100","author":"Sun","year":"2016","journal-title":"J Leukoc Biol"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1186\/s12974-020-01927-w","article-title":"Caspase-1 has a critical role in blood-brain barrier injury and its inhibition contributes to multifaceted repair","volume":"17","author":"Israelov","year":"2020","journal-title":"J Neuroinflammation"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"4922","DOI":"10.1128\/IAI.00417-06","article-title":"Caspase-1-mediated activation of interleukin-1beta (IL-1beta) and IL-18 contributes to innate immune defenses against Salmonella enterica serovar typhimurium infection","volume":"74","author":"Raupach","year":"2006","journal-title":"Infect Immun"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s12944-020-01220-y","article-title":"Caspase-1 as a regulatory molecule of lipid metabolism","volume":"19","author":"Molla","year":"2020","journal-title":"Lipids Health Dis"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"15947","DOI":"10.1074\/jbc.M112.426791","article-title":"Caspase 1 activation is protective against hepatocyte cell death by up-regulating beclin 1 protein and mitochondrial autophagy in the setting of redox stress","volume":"288","author":"Sun","year":"2013","journal-title":"J Biol Chem"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1167\/iovs.02-0437","article-title":"Mildly abnormal retinal function in transgenic mice without Muller cell aquaporin-4 water channels","volume":"43","author":"Li","year":"2002","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"32792","DOI":"10.1074\/jbc.M706321200","article-title":"Retinoschisin (RS1), the protein encoded by the X-linked retinoschisis gene, is anchored to the surface of retinal photoreceptor and bipolar cells through its interactions with a Na\/K ATPase-SARM1 complex","volume":"282","author":"Molday","year":"2007","journal-title":"J Biol Chem"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1080\/13816810.2018.1466340","article-title":"Diurnal variations of foveoschisis by optical coherence tomography in patients with RS1 X-linked juvenile retinoschisis","volume":"39","author":"Abalem","year":"2018","journal-title":"Ophthalmic Genet"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1347599\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T04:29:26Z","timestamp":1718252966000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1347599\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,13]]},"references-count":28,"alternative-id":["10.3389\/fmed.2024.1347599"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2024.1347599","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,13]]},"article-number":"1347599"}}