Exotoxins from Staphylococcus aureus activate 5-lipoxygenase and induce leukotriene biosynthesis
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Exotoxins from Staphylococcus aureus activate 5‑lipoxygenase and induce leukotriene biosynthesis Erik Romp1 · Vandana Arakandy2 · Jana Fischer1 · Christiane Wolz3 · Anke Siegmund2 · Bettina Löffler2 · Lorena Tuchscherr2 · Oliver Werz1 · Ulrike Garscha1 Received: 10 July 2019 / Revised: 14 November 2019 / Accepted: 22 November 2019 © Springer Nature Switzerland AG 2019
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 poreforming 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.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-019-03393-x) contains supplementary material, which is available to authorized users. * Ulrike Garscha ulrike.garscha@uni‑jena.de
Lorena Tuchscherr [email protected]‑jena.de
Erik Romp erik.romp@uni‑jena.de
Oliver Werz oliver.werz@uni‑jena.de
Vandana Arakandy [email protected]‑jena.de
1
Jana Fischer fischer.jana@uni‑jena.de
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, 07743 Jena, Germany
2
Christiane Wolz [email protected]‑tuebingen.de
Institute of Medical Microbiology, University Hospital Jena, 07747 Jena, Germany
3
Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, 72076 Tuebingen, Germany
Anke Siegmund [email protected]‑jena.de Bettina Löffler [email protected]‑jena.de
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E. Romp et al.
Graphic abstract
Keywords Exotoxins · Phenol-soluble modulins · Staphylococcus aureus · Leukotriene · 5-Lipoxygenase
Introduction Inflammation is a complex biological immune response to harmful stimuli including bacteria or fungi to regain homeostasis. Neutrophils are powerful effector cells at sites of inflammation and bacterial invasion that combat the infectious threat by phagocytosis, reactive oxygen species generation, degranulation, formation of antimicrobial neutrophil e
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