Tamoxifen augments the innate immune function of neutrophils through modulation of intracellular ceramide

Ross Corriden (), Andrew Hollands, Joshua Olson, Jaclyn Derieux, Justine Lopez, John T. Chang, David J. Gonzalez and Victor Nizet ()
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Ross Corriden: University of California, San Diego
Andrew Hollands: University of California, San Diego
Joshua Olson: University of California, San Diego
Jaclyn Derieux: University of California, San Diego
Justine Lopez: University of California, San Diego
John T. Chang: University of California, San Diego
David J. Gonzalez: University of California, San Diego
Victor Nizet: University of California, San Diego

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: Abstract Tamoxifen is a selective oestrogen receptor modulator widely used for the treatment of breast cancer. In addition to its activity as an oestrogen receptor agonist/antagonist, tamoxifen also modulates sphingolipid biosynthesis, which has been shown to play an important role in the regulation of neutrophil activity. Here, we find that tamoxifen stimulation enhances several pro-inflammatory pathways in human neutrophils, including chemotaxis, phagocytosis and neutrophil extracellular trap (NET) formation. The enhancement of NET production occurs via a ceramide/PKCζ-mediated pathway, and treatment with synthetic ceramide is sufficient to promote NET formation. Pretreatment of human neutrophils with tamoxifen boosts neutrophil bactericidal capacity against a variety of pathogens in vitro and enhances clearance of the leading human pathogen methicillin-resistant Staphylococcus aureus in vivo. Our results suggest that tamoxifen, and the lipid signalling pathways it modulates, merit further exploration as targets for boosting host innate immune function.

Date: 2015
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DOI: 10.1038/ncomms9369

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