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Ehrnrooths Stiftelse","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100015738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004092","name":"Kuopion Yliopistollinen Sairaala","doi-asserted-by":"publisher","award":["5503743"],"award-info":[{"award-number":["5503743"]}],"id":[{"id":"10.13039\/501100004092","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Suomen Silm\u00e4s\u00e4\u00e4ti\u00f6","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100004212","name":"P\u00e4ivikki ja Sakari Sohlbergin S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100004212","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Inflammation is a key underlying factor of age-related macular degeneration (AMD) and inflammasome activation has been linked to disease development. Induced pluripotent stem-cell-derived retinal pigment epithelial cells (iPSC-RPE) are an attractive novel model system that can help to further elucidate disease pathways of this complex disease. Here, we analyzed the effect of dysfunctional protein clearance on inflammation and inflammasome activation in iPSC-RPE cells generated from a patient suffering from age-related macular degeneration (AMD) and an age-matched control. We primed iPSC-RPE cells with IL-1\u03b1 and then inhibited both proteasomal degradation and autophagic clearance using MG-132 and bafilomycin A1, respectively, causing inflammasome activation. Subsequently, we determined cell viability, analyzed the expression levels of inflammasome-related genes using a PCR array, and measured the levels of pro-inflammatory cytokines IL-1\u03b2, IL-6, IL-8, and MCP-1 secreted into the medium. Cell treatments modified the expression of 48 inflammasome-related genes and increased the secretion of mature IL-1\u03b2, while reducing the levels of IL-6 and MCP-1. Interestingly, iPSC-RPE from an AMD donor secreted more IL-1\u03b2 and expressed more Hsp90 prior to the inhibition of protein clearance, while MCP-1 and IL-6 were reduced at both protein and mRNA levels. Overall, our results suggest that cellular clearance mechanisms might already be dysfunctional, and the inflammasome activated, in cells with a disease origin.<\/jats:p>","DOI":"10.3390\/ijms22136800","type":"journal-article","created":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T11:01:38Z","timestamp":1624532498000},"page":"6800","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Differential Expression of Inflammasome-Related Genes in Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells with or without History of Age-Related Macular Degeneration"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2150-6847","authenticated-orcid":false,"given":"Maria","family":"Hytti","sequence":"first","affiliation":[{"name":"Immuno-Ophthalmology, School of Pharmacy, University of Eastern Finland, 70210 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5360-7258","authenticated-orcid":false,"given":"Eveliina","family":"Korhonen","sequence":"additional","affiliation":[{"name":"Immuno-Ophthalmology, School of Pharmacy, University of Eastern Finland, 70210 Kuopio, Finland"},{"name":"Department of Clinical Chemistry, HUSLAB, Helsinki University Hospital, 00029 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2416-5673","authenticated-orcid":false,"given":"Heidi","family":"Hongisto","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland"},{"name":"Ophthalmology, School of Medicine, University of Eastern Finland, 70210 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Kaarniranta","sequence":"additional","affiliation":[{"name":"Ophthalmology, School of Medicine, University of Eastern Finland, 70210 Kuopio, Finland"},{"name":"Department of Ophthalmology, Kuopio University Hospital, 70029 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4127-8792","authenticated-orcid":false,"given":"Heli","family":"Skottman","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8254-0200","authenticated-orcid":false,"given":"Anu","family":"Kauppinen","sequence":"additional","affiliation":[{"name":"Immuno-Ophthalmology, School of Pharmacy, University of Eastern Finland, 70210 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1016\/j.ophtha.2017.05.035","article-title":"Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future","volume":"124","author":"Colijn","year":"2017","journal-title":"Ophthalmology"},{"key":"ref_2","first-page":"493","article-title":"Updates on the Epidemiology of Age-Related Macular Degeneration","volume":"6","author":"Jonas","year":"2017","journal-title":"Asia Pac. 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