Small-Molecule Inhibitor of 8-Oxoguanine DNA Glycosylase 1 Regulates Inflammatory Responses during Pseudomonas aeruginosa Infection

The DNA repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG1), which excises 8-oxo-7,8-dihydroguanine lesions induced in DNA by reactive oxygen species, has been linked to the pathogenesis of lung diseases associated with bacterial infections. A recently developed small molecule, SU0268, has demonstra...

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Veröffentlicht in:The Journal of immunology (1950) 2020-10, Vol.205 (8), p.2231-2242
Hauptverfasser: Qin, Shugang, Lin, Ping, Wu, Qun, Pu, Qinqin, Zhou, Chuanmin, Wang, Biao, Gao, Pan, Wang, Zhihan, Gao, Ashley, Overby, Madison, Yang, Jinliang, Jiang, Jianxin, Wilson, David L, Tahara, Yu-Ki, Kool, Eric T, Xia, Zhenwei, Wu, Min
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Sprache:eng
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Zusammenfassung:The DNA repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG1), which excises 8-oxo-7,8-dihydroguanine lesions induced in DNA by reactive oxygen species, has been linked to the pathogenesis of lung diseases associated with bacterial infections. A recently developed small molecule, SU0268, has demonstrated selective inhibition of OGG1 activity; however, its role in attenuating inflammatory responses has not been tested. In this study, we report that SU0268 has a favorable effect on bacterial infection both in mouse alveolar macrophages (MH-S cells) and in C57BL/6 wild-type mice by suppressing inflammatory responses, particularly promoting type I IFN responses. SU0268 inhibited proinflammatory responses during (PA14) infection, which is mediated by the KRAS-ERK1-NF-κB signaling pathway. Furthermore, SU0268 induces the release of type I IFN by the mitochondrial DNA-cGAS-STING-IRF3-IFN-β axis, which decreases bacterial loads and halts disease progression. Collectively, our results demonstrate that the small-molecule inhibitor of OGG1 (SU0268) can attenuate excessive inflammation and improve mouse survival rates during PA14 infection. This strong anti-inflammatory feature may render the inhibitor as an alternative treatment for controlling severe inflammatory responses to bacterial infection.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1901533