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Exotoxins from Staphylococcus aureus activate 5-lipoxygenase and induce leukotriene biosynthesis

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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.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (GA2101/2-1, SFB1127 ChemBioSys, and SFB 1278 Polytarget) and SFB-TR156 to C.W., E.R. received a stipend from Landesgraduierten-Akademie Jena. V.A. was supported by the International Leibniz Research School for Microbial and Biomolecular Interactions (ILRS). L.T. and B.L. were supported by the Leibniz Science Campus InfectoOptics SAS-2015-HKI-LWC.

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  1. Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, 07743, Jena, Germany

    Erik Romp, Jana Fischer, Oliver Werz & Ulrike Garscha

  2. Institute of Medical Microbiology, University Hospital Jena, 07747, Jena, Germany

    Vandana Arakandy, Anke Siegmund, Bettina Löffler & Lorena Tuchscherr

  3. Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, 72076, Tuebingen, Germany

    Christiane Wolz

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ER, VA, JF, AS, and CW performed the experiments; ER and UG performed data analysis; ER, OW, and UG designed the study and all authors contributed to the discussion and manuscript preparation.

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Correspondence to Ulrike Garscha.

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Romp, E., Arakandy, V., Fischer, J. et al. Exotoxins from Staphylococcus aureus activate 5-lipoxygenase and induce leukotriene biosynthesis. Cell. Mol. Life Sci. 77, 3841–3858 (2020). https://doi.org/10.1007/s00018-019-03393-x

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