The selective estrogen receptor modulator bazedoxifene affects the metabolism and functions of human neutrophils

Bazedoxifene is a selective estrogen receptor modulator that is prescribed to menopausal women to treat symptoms of estrogen deficiency. Furthermore, bazedoxifene is being considered for cancer therapeutics due to its ability to block IL-6 signaling. However, various selective estrogen receptor modulators have been shown to dysregulate the activation and functions of immune cells. Neutrophils are critical players during inflammation, and these medications have been shown to modulate neutrophil activity. Hence, we hypothesize that bazedoxifene could interact with neutrophils and affect their functions. We collected neutrophils from healthy female and male donors and treated them with bazedoxifene. We assessed neutrophil viability by flow cytometry and their metabolic activity with an extracellular flux analyzer (Seahorse). The production of cytokines, phagocytosis, and the production of reactive oxygen species were measured by ELISA, the uptake of pHrodo-conjugated Escherichia coli, and luminol chemiluminescence, respectively. Finally, estrogen receptor and kinase inhibitors were used to investigate mechanisms of action. High doses of bazedoxifene compromise neutrophil viability in a sex-dependent manner. However, these concentrations can increase the release of inflammatory cytokines while impairing antimicrobial functions in both sexes. The effects of bazedoxifene on neutrophil function are independent of estrogen receptors but may be partially mediated by p38 MAPK activation. Taken together, bazedoxifene could promote neutrophilic inflammation by releasing chemokines while hindering pathogenic clearance. These observations expand our knowledge of the adverse effects of selective estrogen receptor modulators on immune cells, and they highlight the importance of understanding their activity before becoming repurposed to treat chronic conditions.