Key Points Neutrophils produce high levels of Cxcl2 in response to whole bacteria. Cxcl2 production depends on sensing of bacterial nucleic acids by TLR7, 9, and 13. Cxcl2 acts autocrinously to enhance antibacterial activities and its own production. Visual Abstract The influx of neutrophils to infection sites is a fundamental step in host defenses against the frequent human pathogen group B Streptococcus (GBS) and other extracellular bacteria. Using a mouse model of GBS-induced peritonitis, we show in this study that the chemokines Cxcl1 and Cxcl2 play distinctive roles in enhancing the recruitment and the antibacterial activities of neutrophils in a manner that is linked to differences in the cellular sources of these mediators. Cell depletion experiments demonstrated that neutrophils make a significant contribution to the in vivo production of Cxcl2 but not Cxcl1. In vitro, neutrophils responded weakly to LPS but released high levels of Cxcl2 after stimulation with GBS or other bacteria. Neutrophil-derived Cxcl2 acted in an autocrinous manner to increase its own production and to enhance antibacterial activities, including the release of oxygen radicals. In both neutrophils and macrophages, the production of Cxcl1/2 largely required the presence of functional UNC93B1, a chaperone protein involved in signaling by endosomal TLRs. Moreover, the phenotype of UNC93B1-defective phagocytes could be recapitulated by the simultaneous absence of TLR7, 9, and 13 but not by the absence of individual TLRs. Collectively, our data show that neutrophils recognize Gram-positive and Gram-negative bacteria by means of multiple phagosomal TLRs, resulting in de novo synthesis of Cxcl2, amplification of neutrophil recruitment, and potentiation of their antibacterial activities. These data may be useful to devise alternative therapeutic strategies aimed at enhancing the recruitment and the functional activities of polymorphonuclear leukocytes during infections caused by antibiotic-resistant bacteria.

中文翻译：

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中性粒细胞通过内体 TLR 依赖的 Cxcl2 产生增强它们自身对细菌感染部位的流入

要点 中性粒细胞对整个细菌产生高水平的 Cxcl2。Cxcl2 的产生取决于 TLR7、9 和 13 对细菌核酸的感知。Cxcl2 自分泌作用以增强抗菌活性及其自身的产生。视觉摘要 中性粒细胞涌入感染部位是宿主防御常见的人类病原体 B 族链球菌 (GBS) 和其他细胞外细菌的基本步骤。使用 GBS 诱导的腹膜炎小鼠模型，我们在这项研究中表明，趋化因子 Cxcl1 和 Cxcl2 在增强中性粒细胞的募集和抗菌活性方面发挥着独特的作用，这种作用与这些介质的细胞来源的差异有关。细胞耗竭实验表明，中性粒细胞对 Cxcl2 的体内产生有显着贡献，但对 Cxcl1 无贡献。在体外，中性粒细胞对 LPS 反应较弱，但在用 GBS 或其他细菌刺激后释放高水平的 Cxcl2。中性粒细胞衍生的 Cxcl2 以自分泌方式起作用，以增加其自身的产量并增强抗菌活性，包括释放氧自由基。在中性粒细胞和巨噬细胞中，Cxcl1/2 的产生很大程度上需要功能性 UNC93B1 的存在，UNC93B1 是一种参与内体 TLR 信号传导的伴侣蛋白。此外，UNC93B1 缺陷吞噬细胞的表型可以通过同时缺失 TLR7、9 和 13 而不是单个 TLR 的缺失来概括。总的来说，我们的数据显示，中性粒细胞通过多个吞噬体 TLR 识别革兰氏阳性和革兰氏阴性细菌，导致 Cxcl2 的从头合成、中性粒细胞募集的放大和抗菌活性的增强。这些数据可能有助于设计旨在增强多形核白细胞在抗生素抗性细菌引起的感染期间的募集和功能活性的替代治疗策略。