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Enhancement of neutrophil antimicrobial activity by the breast cancer drug tamoxifen
Author(s) -
Flores Roxana,
Insel Paul A,
Nizet Victor,
Corriden Ross
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.969.14
Subject(s) - innate immune system , neutrophil extracellular traps , biology , microbiology and biotechnology , immune system , tamoxifen , estrogen receptor , pharmacology , immunology , inflammation , cancer , breast cancer , genetics
Neutrophils, the primary phagocytic leukocytes in the blood, play a central role in the innate immune response to pathogens such as methicillin‐resistant Staphylococcus aureus (MRSA). Given the rapid emergence of antibiotic resistance and slow development of antibiotics, new approaches to treat infections are urgently needed. We found that the breast cancer drug tamoxifen enhances several pro‐inflammatory pathways in human neutrophils, including chemotaxis, phagocytosis and neutrophil extracellular trap (NET) formation. Microscopy and mass spectrometry revealed that tamoxifen‐induced NET production occurs via an accumulation of intracellular ceramide (specifically C16 and C24 ceramide species) and subsequent activation of PKCζ. In contrast, enhancement of chemotaxis and phagocytosis occur via tamoxifen's agonist activity at the G protein‐coupled estrogen receptor GPER; indeed, G‐36, a selective antagonist of GPER, is a potent inhibitor of these processes. Pretreatment of human neutrophils with tamoxifen boosts neutrophil bactericidal capacity against MRSA, Pseudomonas aeruginosa and Escherichia coli in vitro and enhances survival and bacterial clearance (with 2.4–4.2 log reductions in bacterial counts in peritoneal lavage, blood, kidney, liver and spleen tissue samples) in an in vivo model of MRSA infection. Our results suggest that tamoxifen, and the lipid/GPCR signaling pathways it modulates, appear to be previously unrecognized ways to boost host innate immune function (in particular of neutrophils) and through such actions, to be a novel means to aid in the treatment of infections, especially of antibiotic‐resistant bacteria. Support or Funding Information Research was supported by NIH grants HD071600, AI057153 and AI052453.