Tamoxifen Augments the Innate Immune Function of Neutrophils Through Modulation of Intracellular Ceramide

Abstract

Tamoxifen is a selective estrogen receptor modulator widely used for the treatment of breast cancer. In addition to its activity as an estrogen 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 signaling pathways it modulates, merit further exploration as targets for boosting host innate immune function.