Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, China.
School of Water, Energy and Environment, Cranfield University, Bedfordshire, United Kingdom.
J Infect Dis. 2024 Feb 14;229(2):535-546. doi: 10.1093/infdis/jiad339.
Mastitis caused by antibiotic-resistant strains of Staphylococcus aureus is a significant concern in the livestock industry due to the economic losses it incurs. Regulating immunometabolism has emerged as a promising approach for preventing bacterial inflammation. To investigate the possibility of alleviating inflammation caused by S aureus infection by regulating host glycolysis, we subjected the murine mammary epithelial cell line (EpH4-Ev) to S aureus challenge. Our study revealed that S aureus can colonize EpH4-Ev cells and promote inflammation through hypoxic inducible factor 1α (HIF1α)-driven glycolysis. Notably, the activation of HIF1α was found to be dependent on the production of reactive oxygen species (ROS). By inhibiting PFKFB3, a key regulator in the host glycolytic pathway, we successfully modulated HIF1α-triggered metabolic reprogramming by reducing ROS production in S aureus-induced mastitis. Our findings suggest that there is a high potential for the development of novel anti-inflammatory therapies that safely inhibit the glycolytic rate-limiting enzyme PFKFB3.
金黄色葡萄球菌引起的乳腺炎是畜牧业的一个重大问题，因为它会造成经济损失。调节免疫代谢已成为预防细菌炎症的一种有前途的方法。为了研究通过调节宿主糖酵解来缓解金黄色葡萄球菌感染引起的炎症的可能性，我们用金黄色葡萄球菌对鼠乳腺上皮细胞系（EpH4-Ev）进行了挑战。我们的研究表明，金黄色葡萄球菌可以定植 EpH4-Ev 细胞，并通过缺氧诱导因子 1α（HIF1α）驱动的糖酵解促进炎症。值得注意的是，发现 HIF1α的激活依赖于活性氧（ROS）的产生。通过抑制糖酵解途径中的关键调节因子 PFKFB3，我们成功地通过减少金黄色葡萄球菌诱导的乳腺炎中 ROS 的产生来调节 HIF1α 触发的代谢重编程。我们的研究结果表明，开发安全抑制糖酵解限速酶 PFKFB3 的新型抗炎疗法具有很高的潜力。
