Small-Molecule Inhibitor of 8-Oxoguanine DNA Glycosylase 1 Regulates Inflammatory Responses during Pseudomonas aeruginosa Infection
- 14 September 2020
- journal article
- research article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 205 (8), 2231-2242
- https://doi.org/10.4049/jimmunol.1901533
Abstract
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 Pseudomonas aeruginosa (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.Keywords
Funding Information
- National Institutes of Health (R01 AI109317-01A1, R01 AI138203, AI097532-01A1, CA217809, P20 GM113123, P20 GM103442)
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