Key Points OGG1 inhibitor SU0268 facilitates antibacterial immunity in PA14 infection. SU0268 mitigates bacterial infection via an mtDNA-mediated cGAS pathway. SU0268 attenuates lung injury caused by PA14 infection in vivo. 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.

中文翻译：

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8-氧鸟嘌呤 DNA 糖基化酶 1 的小分子抑制剂在铜绿假单胞菌感染期间调节炎症反应

要点 OGG1 抑制剂 SU0268 促进 PA14 感染中的抗菌免疫。SU0268 通过 mtDNA 介导的 cGAS 途径减轻细菌感染。SU0268 在体内减轻由 PA14 感染引起的肺损伤。DNA 修复酶 8-氧鸟嘌呤 DNA 糖基化酶 1 (OGG1) 可切除由活性氧在 DNA 中诱导的 8-氧-7,8-二氢鸟嘌呤损伤，与细菌感染相关的肺部疾病的发病机制有关。最近开发的小分子 SU0268 已证明选择性抑制 OGG1 活性；然而，它在减轻炎症反应方面的作用尚未经过测试。在这项研究中，我们报告说 SU0268 通过抑制炎症反应对小鼠肺泡巨噬细胞（MH-S 细胞）和 C57BL/6 野生型小鼠中的细菌感染有有利影响，特别是促进 I 型干扰素反应。SU0268 抑制铜绿假单胞菌 (PA14) 感染期间的促炎反应，该反应由 KRAS-ERK1-NF-κB 信号通路介导。此外，SU0268 通过线粒体 DNA-cGAS-STING-IRF3-IFN-β 轴诱导 I 型 IFN 的释放，从而减少细菌负荷并阻止疾病进展。总的来说，我们的结果表明 OGG1 的小分子抑制剂 (SU0268) 可以减轻 PA14 感染期间的过度炎症并提高小鼠的存活率。这种强大的抗炎特性可能使抑制剂成为控制对细菌感染的严重炎症反应的替代疗法。由 KRAS-ERK1-NF-κB 信号通路介导。此外，SU0268 通过线粒体 DNA-cGAS-STING-IRF3-IFN-β 轴诱导 I 型 IFN 的释放，从而减少细菌负荷并阻止疾病进展。总的来说，我们的结果表明 OGG1 的小分子抑制剂（SU0268）可以减轻 PA14 感染期间的过度炎症并提高小鼠的存活率。这种强大的抗炎特性可能使抑制剂成为控制对细菌感染的严重炎症反应的替代疗法。由 KRAS-ERK1-NF-κB 信号通路介导。此外，SU0268 通过线粒体 DNA-cGAS-STING-IRF3-IFN-β 轴诱导 I 型 IFN 的释放，从而减少细菌负荷并阻止疾病进展。总的来说，我们的结果表明 OGG1 的小分子抑制剂 (SU0268) 可以减轻 PA14 感染期间的过度炎症并提高小鼠的存活率。这种强大的抗炎特性可能使抑制剂成为控制对细菌感染的严重炎症反应的替代疗法。我们的结果表明，OGG1 的小分子抑制剂（SU0268）可以减轻 PA14 感染期间的过度炎症并提高小鼠的存活率。这种强大的抗炎特性可能使抑制剂成为控制对细菌感染的严重炎症反应的替代疗法。我们的结果表明，OGG1 的小分子抑制剂（SU0268）可以减轻 PA14 感染期间的过度炎症并提高小鼠的存活率。这种强大的抗炎特性可能使抑制剂成为控制对细菌感染的严重炎症反应的替代疗法。