Sex differences in immune-mediated diseases are linked to the activity of estrogens on innate immunity cells,
including macrophages. Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in estrogen
receptor-alpha (ERα)-dependent breast cancers and off-target indications such as infections, although the immune activity of TAM and its active metabolite, 4-OH tamoxifen (4HT), is poorly characterized. Here, we aimed
at investigating the endocrine and immune activity of these SERMs in macrophages. Using primary cultures of
female mouse macrophages, we analyzed the expression of immune mediators and activation of effector functions in competition experiments with SERMs and 17β-estradiol (E2) or the bacterial endotoxin LPS. We observed
that 4HT and TAM induce estrogen antagonist effects when used at nanomolar concentrations, while pharmacological concentrations that are reached by TAM in clinical settings regulate the expression of VEGFα and other
immune activation genes by ERα- and G protein-coupled receptor 1 (GPER1)-independent mechanisms that
involve NRF2 through PI3K/Akt-dependent mechanisms. Importantly, we observed that SERMs potentiate cell
phagocytosis and modify the effects of LPS on the expression of inflammatory cytokines, such as TNFα and IL1β,
with an overall increase in cell inflammatory phenotype, further sustained by potentiation of IL1β secretion
through caspase-1 activation