Pneumolysin Induces 12-Lipoxygenase-Dependent Neutrophil Migration during Streptococcus pneumoniae Infection
Pneumolysin Induces 12-Lipoxygenase-Dependent Neutrophil Migration during Streptococcus pneumoniae Infection
复制标题
DOI：
10.4049/jimmunol.1800748
复制
发表时间：
2020-01-01
影响因子：
4.4
通讯作者：
Leong, John M.
中科院分区：
文献类型：
--
作者：
Adams, Walter;Bhowmick, Rudra;Leong, John M.
肺炎链球菌是肺炎的主要原因，其中呼吸道粘膜感染驱动中性粒细胞大量涌入。我们之前的研究表明，肺炎链球菌感染呼吸道上皮诱导12-脂氧合酶（12-LOX）依赖的脂质炎症介质hepoxilin A3的产生，其促进中性粒细胞向气道募集，组织损伤和致死性败血症。溶血素（PLY）是胆固醇依赖性细胞溶血素（CDC）家族的一员，是肺炎链球菌的主要毒力因子，在真核膜上产生类似25纳米直径的孔，并促进急性炎症、组织损伤和菌血症。我们表明，ply缺陷肺炎链球菌突变体在体外触发人中性粒细胞经上皮细胞迁移的能力受损。异位产生的PLY赋予非致病性枯草芽孢杆菌触发中性粒细胞在人类培养的单层中募集的能力。纯化的PLY，其他几个CDC家族成员，以及败血性梭菌的a-毒素，产生的孔的横截面积比CDC小近300倍，复制了这种强大的中性粒细胞迁移。在孔隙组装的各个阶段被捕获的PLY非成孔点突变体不能招募中性粒细胞。PLY在体外以12- lox依赖的方式触发中性粒细胞募集。将野生型PLY而非无活性衍生物注入小鼠肺部，诱导了12- lox依赖性中性粒细胞向气道迁移，尽管在12- lox缺乏的小鼠中，PLY诱导的残余炎症表明，12- lox非依赖性途径也有助于PLY引发的肺部炎症。这些数据表明，PLY是促进hepoxilin a3依赖的中性粒细胞以孔隙依赖的方式通过肺上皮募集的重要因素。
Streptococcus pneumoniae is a major cause of pneumonia, wherein infection of respiratory mucosa drives a robust influx of neutrophils. We have previously shown that S. pneumoniae infection of the respiratory epithelium induces the production of the 12-lipoxygenase (12-LOX)-dependent lipid inflammatory mediator hepoxilin A3, which promotes recruitment of neutrophils into the airways, tissue damage, and lethal septicemia. Pneumolysin (PLY), a member of the cholesterol-dependent cytolysin (CDC) family, is a major S. pneumoniae virulence factor that generates similar to 25-nm diameter pores in eukaryotic membranes and promotes acute inflammation, tissue damage, and bacteremia. We show that a PLY-deficient S. pneumoniae mutant was impaired in triggering human neutrophil transepithelial migration in vitro. Ectopic production of PLY endowed the nonpathogenic Bacillus subtilis with the ability to trigger neutrophil recruitment across human-cultured monolayers. Purified PLY, several other CDC family members, and the a-toxin of Clostridium septicum, which generates pores with cross-sectional areas nearly 300 times smaller than CDCs, reproduced this robust neutrophil transmigration. PLY non-pore-forming point mutants that are trapped at various stages of pore assembly did not recruit neutrophils. PLY triggered neutrophil recruitment in a 12-LOX-dependent manner in vitro. Instillation of wild-type PLY but not inactive derivatives into the lungs of mice induced robust 12-LOX-dependent neutrophil migration into the airways, although residual inflammation induced by PLY in 12-LOX-deficient mice indicates that 12-LOX-independent pathways also contribute to PLY-triggered pulmonary inflammation. These data indicate that PLY is an important factor in promoting hepoxilin A3-dependent neutrophil recruitment across pulmonary epithelium in a pore-dependent fashion.