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AEBS inhibition in macrophages: Augmenting reality for SERMs repurposing against infections
Chiara Sfogliarini1, Lien Hong Tran1, Candida Maria Cesta2
1Department of Pharmaceutical Sciences, University of Milan, Milan, Italy.
Abstract:
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.
Insights
Selective estrogen receptor modulators (SERMs) show antimicrobial activity by targeting the antiestrogen binding site (AEBS), independent of estrogen receptors. This AEBS inhibition boosts macrophage immune responses against pathogens.
Area of Science:
- Immunology
- Pharmacology
- Infectious Diseases
Background:
- Selective estrogen receptor modulators (SERMs), like raloxifene and tamoxifen, are known for clinical use but also exhibit antimicrobial properties.
- The precise mechanisms behind SERMs' antimicrobial efficacy, independent of classic estrogen receptors, are not fully understood, hindering drug repurposing efforts.
- Macrophages play a crucial role in innate immunity by altering their metabolic state, with cholesterol metabolism being central to immune response and pathogen/host cell requirements.
Purpose of the Study:
- To explore the hypothesis that the microsomal antiestrogen binding site (AEBS) is a key pre-genomic target for SERMs' immunomodulatory and antimicrobial activities.
- To elucidate the mechanisms by which SERMs enhance macrophage antimicrobial functions.
Main Methods:
- Review of recent findings from the authors' laboratory and other research groups.
- Focus on the role of the antiestrogen binding site (AEBS) in cholesterol biosynthesis and its interaction with SERMs.
- Analysis of downstream effects of AEBS inhibition on macrophage inflammatory and antimicrobial pathways.
Main Results:
- SERMs bind with high affinity to the AEBS, a complex of enzymes in late-stage cholesterol biosynthesis.
- Inhibition of AEBS by SERMs leads to cholesterol restriction.
- This cholesterol restriction potentiates macrophage antimicrobial and inflammatory pathways, including inflammasome activation, Toll-like receptor (TLR) modulation, and induction of IRF3 and NRF2-mediated transcription.
- SERMs also mitigate excessive inflammation and proliferation, enhancing overall macrophage response to infection.
Conclusions:
- The AEBS multiprotein complex is a likely pre-genomic target for the immunomodulatory effects of SERMs.
- SERMs-induced cholesterol restriction by AEBS inhibition enhances macrophage antimicrobial defense mechanisms.
- Repurposing SERMs may offer novel strategies for combating a broad range of human pathogens by boosting innate immunity.
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