title: Tamoxifen augments the innate immune function of neutrophils through modulation of intracellular ceramide.
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.
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California 92093, USA.|Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Corriden
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hollands
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA.|Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Derieux
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Justine
authors.initials: J
authors.lastname: Lopez
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Chang
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA.|Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gonzalez
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California 92093, USA.|Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA.|Rady Children's Hospital, San Diego, California 92123, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000818:Animals; D002518:Ceramides / Q000378:metabolism*; D065206:Extracellular Traps / Q000187:drug effects*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus; D051379:Mice; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D002518:Ceramides; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C087857:protein kinase C gamma; D011493:Protein Kinase C