Exotoxins from Staphylococcus aureus activate 5-lipoxygenase and induce leukotriene biosynthesis
Exotoxins from Staphylococcus aureus activate 5-lipoxygenase and induce leukotriene biosynthesis
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DOI：
10.1007/s00018-019-03393-x
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发表时间：
2019-12-05
影响因子：
8
通讯作者：
Garscha, Ulrike
中科院分区：
文献类型：
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作者：
Romp, Erik;Arakandy, Vandana;Garscha, Ulrike
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生成。LTB 4的生物合成是由5-脂氧合酶（5-LOX）介导的，但在细菌感染期间哪些致病因素导致5-LOX活化是不明确的。在这里，我们揭示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，而不是外毒素缺陷型菌株诱导5-LOX激活转染HEK 293细胞。两种不同的葡萄球菌外毒素模拟了S。金黄色条件培养基：（1）孔形成毒素α-溶血素和（2）两亲性α-螺旋酚可溶性调制蛋白（PSM）肽。有趣的是，在人中性粒细胞中，5-LOX活化仅由PSM引起，这被选择性FPR 2/ALX受体拮抗剂WRW 4阻止。5-在体内证实了PSM对LOX的激活作用，因为在受感染的小鼠爪中，由于PSM缺陷的S.金黄色。因此，S.金黄色葡萄球菌是激活5-LOX并诱导嗜中性粒细胞中LT形成的有效致病因子。[图形]。
Massive neutrophil infiltration is an early key event in infectious inflammation, accompanied by chemotactic leukotriene (LT)B-4 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 alpha-hemolysin and (2) amphipathic alpha-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.[GRAPHICS].