title: The Selective Estrogen Receptor Modulator Raloxifene Inhibits Neutrophil Extracellular Trap Formation.
abstract: Raloxifene is a selective estrogen receptor modulator typically prescribed for the prevention/treatment of osteoporosis in postmenopausal women. Although raloxifene is known to have anti-inflammatory properties, its effects on human neutrophils, the primary phagocytic leukocytes of the immune system, remain poorly understood. Here, through a screen of pharmacologically active small molecules, we find that raloxifene prevents neutrophil cell death in response to the classical activator phorbol 12-myristate 13-acetate (PMA), a compound known to induce formation of DNA-based neutrophil extracellular traps (NETs). Inhibition of PMA-induced NET production by raloxifene was confirmed using quantitative and imaging-based assays. Human neutrophils from both male and female donors express the nuclear estrogen receptors ERα and ERβ, known targets of raloxifene. Similar to raloxifene, selective antagonists of these receptors inhibit PMA-induced NET production. Furthermore, raloxifene inhibited PMA-induced ERK phosphorylation, but not reactive oxygen species production, pathways known to be key modulators of NET production. Finally, we found that raloxifene inhibited PMA-induced, NET-based killing of the leading human bacterial pathogen, methicillin-resistantStaphylococcus aureus. Our results reveal that raloxifene is a potent modulator of neutrophil function and NET production.
authors.affiliation: Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics, University of California San Diego , La Jolla, CA , USA.
authors.forename: Roxana
authors.initials: R
authors.lastname: Flores
authors.affiliation: Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics, University of California San Diego , La Jolla, CA , USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Döhrmann
authors.affiliation: Department of Physiological Chemistry, University for Veterinary Medicine Hannover , Hanover , Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Schaal
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School , Boston, MA , USA.
authors.forename: Abdul
authors.initials: A
authors.lastname: Hakkim
authors.affiliation: Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics, University of California San Diego , La Jolla, CA , USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.affiliation: Department of Pharmacology, University of California San Diego , La Jolla, CA , USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Corriden
keywords: MRSA; extracellular traps; host–pathogen interactions; neutrophils; raloxifene