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

  • J Immunol. 2020 Oct 15;205(8):2231-2242. doi: 10.4049/jimmunol.1901533.
Shugang Qin  1  2 ,  Ping Lin  2  3 ,  Qun Wu  2  4 ,  Qinqin Pu  1  2 ,  Chuanmin Zhou  5 ,  Biao Wang  2 ,  Pan Gao  1  2 ,  Zhihan Wang  2  6 ,  Ashley Gao  2 ,  Madison Overby  2 ,  Jinliang Yang  1 ,  Jianxin Jiang  3 ,  David L Wilson  7 ,  Yu-Ki Tahara  7 ,  Eric T Kool  8 ,  Zhenwei Xia  9 ,  Min Wu  10
Affiliations
  • 1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China.
  • 2. Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203.
  • 3. State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, The Third Military Medical University, Chongqing 400042, China.
  • 4. Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 5. Wuhan University School of Health Sciences, Wuhan, Hubei Province 430071, China.
  • 6. West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, China; and.
  • 7. Department of Chemistry, Stanford Cancer Institute, and Chemistry, Engineering and Medicine for Human Health Institute, Stanford University, Stanford, CA 94305.
  • 8. Department of Chemistry, Stanford Cancer Institute, and Chemistry, Engineering and Medicine for Human Health Institute, Stanford University, Stanford, CA 94305 [email protected] [email protected] [email protected].
  • 9. Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; [email protected] [email protected] [email protected].
  • 10. Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203; [email protected] [email protected] [email protected].
PMID: 32929043 DOI: 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.

Products