Department of Pathology, Immunology and Laboratory Medicine, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark New Jersey United States of America.
PLoS Pathog. 2024 Oct 17;20(10):e1012648. doi: 10.1371/journal.ppat.1012648. eCollection 2024 Oct.
Staphylococcus aureus is a versatile bacterium responsible for conditions ranging from mild skin and soft-tissue infections to serious disorders such as pneumonia and sepsis. Monocytes play a role in protection against pathogens by migrating to inflamed tissues and differentiating into macrophages but their specific role in the context of S. aureus pulmonary infection has not been fully elucidated. Using a CCR2-DTR transgenic mouse model we demonstrate that over the course of infection monocyte depletion resulted in worse airway clearance of S. aureus. The bronchoalveolar lavage fluid (BALF) of CCR2-DTR mice after S. aureus infection displayed significant decreases in interleukin-12 (IL-12), IFN-γ, IP-10, MIG and RANTES, all IFN-γ regulated, compared to wild-type (WT) infected controls. NK cells were identified as the main producers of IFN-γ, but both NK cells and IFN-γ were dispensable for clearance. We demonstrated through cytokine production and RNA-seq analysis that IL-12 and IL-12 regulated genes are strongly induced in monocytes upon S. aureus infection. Administration of IL-12 during infection restored the bacterial burdens in the BALF and lungs of monocyte-depleted CCR2-DTR mice to the levels of WT mice, independent of IFN-γ. In the absence of monocytes, alveolar macrophages are the primary phagocytic cells, and IL-12 influences their capacity to produce reactive oxygen species and clear S. aureus. These results show that production of IL-12 contributes to the control of S. aureus via its influence on alveolar macrophage function.
金黄色葡萄球菌是一种多功能细菌，可引起从轻度皮肤和软组织感染到肺炎和败血症等严重疾病。单核细胞通过迁移到炎症组织并分化为巨噬细胞来发挥保护作用，但它们在金黄色葡萄球菌肺部感染中的具体作用尚未完全阐明。使用 CCR2-DTR 转基因小鼠模型，我们证明在感染过程中单核细胞耗竭会导致金黄色葡萄球菌的气道清除能力下降。与野生型（WT）感染对照相比，金黄色葡萄球菌感染后 CCR2-DTR 小鼠的支气管肺泡灌洗液（BALF）中白细胞介素-12（IL-12）、IFN-γ、IP-10、MIG 和 RANTES 的含量均显著降低，这些细胞因子均受 IFN-γ 调控。NK 细胞被鉴定为 IFN-γ的主要产生细胞，但 NK 细胞和 IFN-γ对于清除金黄色葡萄球菌均不是必需的。我们通过细胞因子产生和 RNA-seq 分析表明，IL-12 和 IL-12 调控的基因在单核细胞感染金黄色葡萄球菌后被强烈诱导。在感染期间给予 IL-12 可将单核细胞耗竭的 CCR2-DTR 小鼠 BALF 和肺部的细菌负荷恢复到 WT 小鼠的水平，而不依赖于 IFN-γ。在没有单核细胞的情况下，肺泡巨噬细胞是主要的吞噬细胞，IL-12 影响其产生活性氧和清除金黄色葡萄球菌的能力。这些结果表明，IL-12 的产生通过影响肺泡巨噬细胞的功能有助于金黄色葡萄球菌的控制。
