Cellular and Molecular Life Sciences ( IF 6.2 ) Pub Date : 2019-12-05 , DOI: 10.1007/s00018-019-03393-x Erik Romp 1 , Vandana Arakandy 2 , Jana Fischer 1 , Christiane Wolz 3 , Anke Siegmund 2 , Bettina Löffler 2 , Lorena Tuchscherr 2 , Oliver Werz 1 , Ulrike Garscha 1
|
Abstract
Massive neutrophil infiltration is an early key event in infectious inflammation, accompanied by chemotactic leukotriene (LT)B4 generation. LTB4 biosynthesis is mediated by 5-lipoxygenase (5-LOX), but which pathogenic factors cause 5-LOX activation during bacterial infections is elusive. Here, we reveal staphylococcal exotoxins as 5-LOX activators. Conditioned medium of wild-type Staphylococcus aureus but not of exotoxin-deficient strains induced 5-LOX activation in transfected HEK293 cells. Two different staphylococcal exotoxins mimicked the effects of S. aureus-conditioned medium: (1) the pore-forming toxin α-hemolysin and (2) amphipathic α-helical phenol-soluble modulin (PSM) peptides. Interestingly, in human neutrophils, 5-LOX activation was exclusively evoked by PSMs, which was prevented by the selective FPR2/ALX receptor antagonist WRW4. 5-LOX activation by PSMs was confirmed in vivo as LT formation in infected paws of mice was impaired in response to PSM-deficient S. aureus. Conclusively, exotoxins from S. aureus are potent pathogenic factors that activate 5-LOX and induce LT formation in neutrophils.
Graphic abstract
中文翻译：
金黄色葡萄球菌的外毒素可激活 5-脂氧合酶并诱导白三烯生物合成。
抽象的
大量中性粒细胞浸润是感染性炎症的早期关键事件，伴随着趋化性白三烯 (LT)B 4的产生。 LTB 4生物合成由 5-脂氧合酶 (5-LOX) 介导，但在细菌感染期间哪些致病因素导致 5-LOX 激活尚不清楚。在这里，我们揭示了葡萄球菌外毒素作为 5-LOX 激活剂。野生型金黄色葡萄球菌的条件培养基（而非外毒素缺陷菌株的条件培养基）在转染的 HEK293 细胞中诱导 5-LOX 活化。两种不同的葡萄球菌外毒素模仿了金黄色葡萄球菌条件培养基的作用：(1) 成孔毒素α-溶血素和(2) 两亲性α-螺旋酚溶性调节蛋白(PSM) 肽。有趣的是，在人类中性粒细胞中，5-LOX 激活完全由 PSM 引起，而选择性 FPR2/ALX 受体拮抗剂 WRW4 可以阻止这种激活。 PSM 的 5-LOX 激活在体内得到了证实，因为受感染的小鼠爪子中 LT 的形成因对 PSM 缺陷的金黄色葡萄球菌的反应而受损。总之，金黄色葡萄球菌的外毒素是激活 5-LOX 并诱导中性粒细胞中 LT 形成的有效致病因子。
京公网安备 11010802027423号