2. Academic Validation
  3. Small-Molecule Inhibitor of 8-Oxoguanine DNA Glycosylase 1 Regulates Inflammatory Responses during Pseudomonas aeruginosa Infection

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

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.

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