Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, 450 Technology Drive, Pittsburgh, PA 15219, USA.
Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7450, USA.
Cell Rep. 2024 Jul 23;43(7):114486. doi: 10.1016/j.celrep.2024.114486. Epub 2024 Jul 10.
Skin/soft tissue infections (SSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) pose a major healthcare burden. Distinct inflammatory and resolution phases comprise the host immune response to SSTIs. Resolution is a myeloid PPARγ-dependent anti-inflammatory phase that is essential for the clearance of MRSA. However, the signals activating PPARγ to induce resolution remain unknown. Here, we demonstrate that myeloid glucose transporter 1 (GLUT-1) is essential for the onset of resolution. MRSA-challenged macrophages are unsuccessful in generating an oxidative burst or immune radicals in the absence of GLUT-1 due to a reduction in the cellular NADPH pool. This translates in vivo as a significant reduction in lipid peroxidation products required for the activation of PPARγ in MRSA-infected mice lacking myeloid GLUT-1. Chemical induction of PPARγ during infection circumvents this GLUT-1 requirement and improves resolution. Thus, GLUT-1-dependent oxidative burst is essential for the activation of PPARγ and subsequent resolution of SSTIs.
耐甲氧西林金黄色葡萄球菌（MRSA）引起的皮肤/软组织感染（SSTIs）给医疗保健带来了巨大负担。宿主对 SSTIs 的免疫反应包括明显的炎症和消退两个阶段。消退是一个髓系过氧化物酶体增殖物激活受体γ（PPARγ）依赖性抗炎阶段，对清除 MRSA 至关重要。然而，激活 PPARγ 以诱导消退的信号仍然未知。在这里，我们证明髓系葡萄糖转运蛋白 1（GLUT-1）是消退开始所必需的。由于细胞 NADPH 池减少，MRSA 挑战的巨噬细胞由于无法产生氧化爆发或免疫自由基，因此无法成功产生。这在体内转化为在缺乏髓系 GLUT-1 的 MRSA 感染小鼠中，用于激活 PPARγ 的脂质过氧化产物的显著减少。在感染期间化学诱导 PPARγ 可规避这种 GLUT-1 需求并改善消退。因此，GLUT-1 依赖性氧化爆发对于激活 PPARγ 和随后的 SSTIs 消退是必需的。
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