Neutrophils Enhance Their Own Influx to Sites of Bacterial Infection via Endosomal TLR-Dependent Cxcl2 Production
Neutrophils Enhance Their Own Influx to Sites of Bacterial Infection via Endosomal TLR-Dependent Cxcl2 Production
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DOI：
10.4049/jimmunol.1901039
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发表时间：
2020-02-01
影响因子：
4.4
通讯作者：
Midiri, Angelina
中科院分区：
文献类型：
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作者：
Lentini, Germana;Fama, Agata;Midiri, Angelina
中性粒细胞进入感染部位是宿主抵御常见的人类病原体B组链球菌(GBS)和其他细胞外细菌的基本步骤。利用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在促进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，中性粒细胞对体内CxCL2的产生有显著贡献，但对CXCL1的产生没有影响。在体外，中性粒细胞对内毒素的反应弱，但在GBS或其他细菌刺激下释放高水平的CxCl2。中性粒细胞来源的CxCl2以自分泌的方式增加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的产生在很大程度上需要有功能的uc93B1的存在，这是一种参与内体TLRs信号传递的伴侣蛋白。此外，可以通过同时缺失TLR7、9和13而不是通过单独缺失TLR来重现UNC93B1缺陷吞噬细胞的表型。综上所述，我们的数据显示，中性粒细胞通过多个吞噬小体TLR识别革兰氏阳性和革兰氏阴性细菌，导致CxCl2从头合成，中性粒细胞募集放大，并增强其抗菌活性。这些数据可能有助于设计替代治疗策略，旨在加强多形核白细胞在耐药细菌感染期间的招募和功能活动。
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.