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- W4366184466 abstract "Ultraviolet (UV) light promotes upregulation of type I interferons (IFNs), which contribute to propensity for skin disease in lupus patients. It is thought that nucleic acids contribute to these IFN responses, yet their cellular source remains unknown. Here, we investigated how UV light and type I IFN exposure impact mitochondrial stress and Z-DNA formation, a left-handed dsDNA primarily localized in mitochondria which may lead to type I IFN production through activation of cGAS. After UV light exposure, immortalized keratinocytes (NTERTs) showed significantly upregulated gene expression of IFNB, IFNK, IFNL, MX1 and OASL. This upregulation was significantly inhibited by preincubation with the mitochondrially targeted antioxidant mitoTEMPO, indicating mitochondrial reactive oxygen species as drivers of UV-dependent IFN responses. To further understand mitochondrial dynamics, confocal microscopy was used. Staining for TOMM20, a mitochondrial outer membrane protein, revealed significant mitochondrial fragmentation after UV light and IFN-α treatment. Intriguingly, cytosolic Z-DNA puncta were increased after IFN-α stimulation and were strongly enhanced after UV irradiation. These puncta were in close association with fragmented mitochondria. MitoTEMPO prevented mitochondrial fragmentation induced by UV and IFN-α and stabilized Z-DNA within the mitochondrial network. Collectively, our data indicate that type I IFN priming, coupled with UV light exposure, results in mitochondrial stress that leads to increased Z-DNA formation within mitochondria and cytoplasmic release. This supports a model in which chronic IFN exposure and mitochondrial-derived Z-DNA stimulate cGAS activation to result in enhanced type I IFN production. This signaling pathway could explain the propensity for photosensitivity observed in lupus patients and requires further study." @default.
- W4366184466 created "2023-04-19" @default.
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- W4366184466 date "2023-05-01" @default.
- W4366184466 modified "2023-09-28" @default.
- W4366184466 title "1167 Mitochondrial Z-DNA as a potential activator of UV-driven interferon responses in keratinocytes" @default.
- W4366184466 doi "https://doi.org/10.1016/j.jid.2023.03.1180" @default.
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