Department of Microbiology, University of Virginia, Charlottesville.
Department of Immunology, University of Virginia, Charlottesville.
J Infect Dis. 2018 Oct 5;218(10):1663-1674. doi: 10.1093/infdis/jiy347.
Infection with Neisseria gonorrhoeae (GC) is characterized by robust neutrophil influx that is insufficient to clear the bacteria. Sustained neutrophilic inflammation contributes to serious clinical sequelae that particularly affect women, including pelvic inflammatory disease and infertility.
We established a 3-component system using GC, End1 polarized human endocervical cells, and primary human neutrophils to investigate neutrophil transepithelial migration following infection.
Neutrophil migration across endocervical monolayers increased with the infectious dose and required GC-epithelial cell contact. Epithelial protein kinase C, cytosolic phospholipase A2, 12R-lipoxygenase (LOX), and eLOX3 hepoxilin synthase were required for neutrophil transmigration to GC, and migration was abrogated by blocking the MRP2 efflux pump and by adding recombinant soluble epoxide hydrolase. These results are all consistent with epithelial cell production of the neutrophil chemoattractant hepoxilin A3 (HXA3). Neutrophil transmigration was also accompanied by increasing apical concentrations of leukotriene B4 (LTB4). Neutrophil 5-lipoxygenase and active BLT1 receptor were required for apical LTB4 and neutrophil migration.
Our data support a model in which GC-endocervical cell contact infection stimulates HXA3 production, driving neutrophil migration that is amplified by neutrophil-derived LTB4. Therapeutic targeting of these pathways could limit inflammation and deleterious clinical sequelae in women with gonorrhea.
淋病奈瑟菌（GC）感染的特征是大量中性粒细胞浸润，但这不足以清除细菌。持续的中性粒细胞炎症导致严重的临床后果，特别是对女性，包括盆腔炎和不孕。
我们建立了一个由 GC、End1 极化的人宫颈内细胞和原代人中性粒细胞组成的 3 组分系统，以研究感染后中性粒细胞跨上皮迁移。
中性粒细胞穿过宫颈上皮细胞单层的迁移随感染剂量的增加而增加，并且需要 GC-上皮细胞接触。上皮蛋白激酶 C、胞质型磷脂酶 A2、12R-脂氧合酶（LOX）和 eLOX3 血栓素合成酶是中性粒细胞向 GC 迁移所必需的，并且通过阻断 MRP2 外排泵和添加重组可溶性环氧水解酶可以阻断迁移。这些结果均与上皮细胞产生中性粒细胞趋化因子血栓素 A3（HXA3）一致。中性粒细胞迁移也伴随着白三烯 B4（LTB4）的顶部分泌浓度增加。中性粒细胞 5-脂氧合酶和活性 BLT1 受体是顶部分泌 LTB4 和中性粒细胞迁移所必需的。
我们的数据支持这样一种模型，即 GC-宫颈内细胞接触感染刺激 HXA3 的产生，驱动中性粒细胞迁移，而中性粒细胞衍生的 LTB4 则放大了这种迁移。针对这些途径的治疗性靶向可能会限制淋病女性的炎症和有害的临床后果。
