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

Maria Hytti, Eveliina Korhonen, Heidi Hongisto, Kai Kaarniranta, Heli Skottman, Anu Kauppinen

    Research output: Contribution to journalArticleScientificpeer-review

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    Abstract

    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-1α 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-1β, 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-1β, while reducing the levels of IL-6 and MCP-1. Interestingly, iPSC-RPE from an AMD donor secreted more IL-1β 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.

    Original languageEnglish
    Article number6800
    JournalInternational Journal of Molecular Sciences
    Volume22
    Issue number13
    DOIs
    Publication statusPublished - Jun 2021
    Publication typeA1 Journal article-refereed

    Keywords

    • Age-related macular degeneration
    • Induced pluripotent stem cells
    • Inflammasomes
    • Inflammation
    • Retinal pigment epithelium

    Publication forum classification

    • Publication forum level 1

    ASJC Scopus subject areas

    • Catalysis
    • Molecular Biology
    • Spectroscopy
    • Computer Science Applications
    • Physical and Theoretical Chemistry
    • Organic Chemistry
    • Inorganic Chemistry

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