Oxidized base 8-oxoguanine, a product of DNA repair processes, contributes to dendritic cell activation

K. Pázmándi, Máté Sütő, Tünde Fekete, Aliz Varga, Eszter Boldizsár, István Boldogh, Attila Bácsi

    Research output: Contribution to journalArticlepeer-review

    1 Scopus citations

    Abstract

    A growing body of evidence suggests that elevated levels of reactive oxygen species (ROS) in the airways caused by exposure to gas phase pollutants or particulate matter are able to activate dendritic cells (DCs); however, the exact mechanisms are still unclear. When present in excess, ROS can modify macromolecules including DNA. One of the most abundant DNA base lesions is 7,8-dihydro-8-oxoguanine (8-oxoG), which is repaired by the 8-oxoguanine DNA glycosylase 1 (OGG1)-initiated base excision repair (BER) (OGG1-BER) pathway. Studies have also demonstrated that in addition to its role in repairing oxidized purines, OGG1 has guanine nucleotide exchange factor activity when bound to 8-oxoG. In the present study, we tested the hypothesis that exposure to 8-oxoG, the specific product of OGG1-BERBER, induces functional changes of DCs. Supporting our hypothesis, transcriptome analysis revealed that in mouse lungs, out of 95 genes associated with DCs’ function, 22 or 42 were significantly upregulated after a single or multiple intranasal 8-oxoG challenges, respectively. In a murine model of allergic airway inflammation, significantly increased serum levels of ovalbumin (OVA)-specific IgE antibodies were detected in mice sensitized via nasal challenges with OVA+8-oxoG compared to those challenged with OVA alone. Furthermore, exposure of primary human monocyte-derived DCs (moDC) to 8-oxoG base resulted in significantly enhanced expression of cell surface molecules (CD40, CD86, CD83, HLA-DQ) and augmented the secretion of pro-inflammatory mediators IL-6, TNF and IL-8, whereas it did not considerably influence the production of the anti-inflammatory cytokine IL-10. The stimulatory effects of 8-oxoG on human moDCs were abolished upon siRNA-mediated OGG1 depletion. Collectively, these data suggest that OGG1-BER-generated 8-oxoG base-driven cell signaling activates DCs, which may contribute to initiation of both the innate and adaptive immune responses under conditions of oxidative stress.

    Original languageEnglish (US)
    Pages (from-to)209-220
    Number of pages12
    JournalFree Radical Biology and Medicine
    Volume143
    DOIs
    StatePublished - Nov 1 2019

    Keywords

    • 7
    • 8-Dihydro-8-oxoguanine
    • 8-Oxoguanine DNA glycosylase 1
    • DNA base excision repair process
    • Dendritic cell activation

    ASJC Scopus subject areas

    • Biochemistry
    • Physiology (medical)

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