AEBS inhibition in macrophages: Augmenting reality for SERMs repurposing against infections

Beyond their clinical use as selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen have attracted recent attention for their favorable activity against a broad range of dangerous human pathogens. While consistently demonstrated to occur independently on classic estrogen receptors, the mechanisms underlying SERMs antimicrobial efficacy remain still poorly elucidated, but fundamental to benefit from repurposing strategies of these drugs. Macrophages are innate immune cells that protect from infections by rapidly reprogramming their metabolic state, particularly cholesterol disposal, which is at the center of an appropriate macrophage immune response as well as of the anabolic requirements of both the pathogen and the host cells. The microsomal antiestrogen binding site (AEBS) comprises enzymes involved in the last stages of cholesterol biosynthesis and is a high affinity off-target site for SERMs. We review here recent findings from our laboratory and other research groups in support of the hypothesis that AEBS multiprotein complex represents the candidate pre-genomic target of SERMs immunomodulatory activity. The cholesterol restriction resulting from SERMs-mediated AEBS inhibition may be responsible for boosting inflammatory and antimicrobial pathways that include inflammasome activation, modulation of Toll-like receptors (TLRs) responses, induction of interferon regulatory factor (IRF3) and nuclear factor erythroid 2-related factor 2 (NRF2)-mediated transcriptional programs and, noteworthy, the mitigation of excessive inflammatory and proliferative responses, leading to the overall potentiation of the macrophage response to infections.