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Article ; Online: The Use of ERE-Luc Reporter Mice to Monitor Estrogen Receptor Transcriptional Activity in a Spatio-Temporal Dimension.

Della Torre, Sara / Vegeto, Elisabetta / Ciana, Paolo

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2418, Page(s) 153–172

Abstract: In spite of the fact that women spend 1/3 of their lives in postmenopause, the search for appropriate therapies able to counteract the derangements associated with the menopause still represents a sort of sought after the "Holy Grail."Nowadays, the ... ...

Abstract	In spite of the fact that women spend 1/3 of their lives in postmenopause, the search for appropriate therapies able to counteract the derangements associated with the menopause still represents a sort of sought after the "Holy Grail."Nowadays, the combination of estrogens and selective estrogen receptor modulators (SERMs), a class of compounds with a mixed agonist/antagonistic activity on the estrogen receptor (ER) in various tissues, represents the most promising approach to improve postmenopausal women's health, by preserving the benefits while avoiding the side effects of estrogen-based therapy.Given their complex mechanisms of action, the evaluation of SERM activity in combination with conjugated estrogens (CE) requires a multifactorial analysis that takes into account the multifaceted and dynamic effects of these compounds in target tissues, even in relation to the physiological/pathological status.To accomplish such a goal, we took advantage of the ERE-Luc model, a reporter mouse that allows the monitoring of ER transcriptional activity in a spatio-temporal dimension. Cluster analyses performed on in vivo/ex vivo bioluminescence (BLI) data and ex vivo luciferase activity enabled to sustain the combination of CE plus bazedoxifene (TSEC, tissue-selective estrogen complex) as a valuable option for the pharmacological treatment of the postmenopause.
MeSH term(s)	Animals ; Estrogens/pharmacology ; Estrogens, Conjugated (USP)/adverse effects ; Female ; Humans ; Menopause ; Mice ; Receptors, Estrogen/genetics ; Selective Estrogen Receptor Modulators/pharmacology ; Selective Estrogen Receptor Modulators/therapeutic use
Chemical Substances	Estrogens ; Estrogens, Conjugated (USP) ; Receptors, Estrogen ; Selective Estrogen Receptor Modulators
Language	English
Publishing date	2022-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-1920-9_10
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Article ; Online: Sex-oriented perspectives in immunopharmacology.

Cignarella, Andrea / Vegeto, Elisabetta / Bolego, Chiara / Trabace, Luigia / Conti, Lucia / Ortona, Elena

Pharmacological research

2023 Volume 197, Page(s) 106956

Abstract: Several immunopharmacological agents are effective in the treatment of cancer and immune-mediated conditions, with a favorable impact on life expectancy and clinical outcomes for a large number of patients. Nevertheless, response variation and ... ...

Abstract	Several immunopharmacological agents are effective in the treatment of cancer and immune-mediated conditions, with a favorable impact on life expectancy and clinical outcomes for a large number of patients. Nevertheless, response variation and undesirable effects of these drugs represent major issues, and overall efficacy remains unpredictable. Males and females show a distinct difference in immune system responses, with females generally mounting stronger responses to a variety of stimuli. Therefore, exploring sex differences in the efficacy and safety of immunopharmacological agents would strengthen the practice of precision medicine. As a pharmacological target highlight, programmed cell death 1 ligand 1 (PD-L1) is the first functionally characterized ligand of the coinhibitory programmed death receptor 1 (PD-1). The PD-L1/PD-1 crosstalk plays an important role in the immune response and is relevant in cancer, infectious and autoimmune disease. Sex differences in the response to immune checkpoint inhibitors are well documented, with male patients responding better than female patients. Similarly, higher efficacy of and adherence to tumor necrosis factor inhibitors in chronic inflammatory conditions including rheumatoid arthritis and Crohn's disease have been reported in male patients. The pharmacological basis of sex-specific responses to immune system modulating drugs is actively investigated in other settings such as stroke and type 1 diabetes. Advances in therapeutics targeting the endothelium could soon be wielded against autoimmunity and metabolic disorders. Based on the established sexual dimorphism in immune-related pathophysiology and disease presentation, sex-specific immunopharmacological protocols should be integrated into clinical guidelines.
MeSH term(s)	Humans ; Male ; Female ; B7-H1 Antigen ; Programmed Cell Death 1 Receptor ; Neoplasms/drug therapy ; Immune Checkpoint Inhibitors/therapeutic use ; Autoimmunity
Chemical Substances	B7-H1 Antigen ; Programmed Cell Death 1 Receptor ; Immune Checkpoint Inhibitors
Language	English
Publishing date	2023-10-17
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1003347-6
ISSN	1096-1186 ; 0031-6989 ; 1043-6618
ISSN (online)	1096-1186
ISSN	0031-6989 ; 1043-6618
DOI	10.1016/j.phrs.2023.106956
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Article ; Online: The immune activity of selective estrogen receptor modulators is gene and macrophage subtype-specific yet converges on Il1b downregulation.

Sfogliarini, Chiara / Pepe, Giovanna / Cesta, Candida Maria / Allegretti, Marcello / Locati, Massimo / Vegeto, Elisabetta

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2023 Volume 165, Page(s) 115008

Abstract: Raloxifene belongs to the family of Selective Estrogen Receptor Modulators (SERMs), which are drugs widely prescribed for Estrogen Receptor alpha (ERα)-related pathologies. Recently, SERMs are being tested in repurposing strategies for ERα-independent ... ...

Abstract	Raloxifene belongs to the family of Selective Estrogen Receptor Modulators (SERMs), which are drugs widely prescribed for Estrogen Receptor alpha (ERα)-related pathologies. Recently, SERMs are being tested in repurposing strategies for ERα-independent clinical indications, including a wide range of microbial infections. Macrophages are central in the fight against pathogen invasion. Despite estrogens have been shown to regulate macrophage phenotype, SERMs activity in these cells is still poorly defined. We investigated the activity of Raloxifene in comparison with another widely used SERM, Tamoxifen, on immune gene expression in macrophages obtained from mouse and human tissues, including mouse peritoneal macrophages, bone marrow-derived macrophages, microglia or human blood-derived macrophages, assaying for the involvement of the ERα, PI3K and NRF2 pathways also under inflammatory conditions. Our data demonstrate that Raloxifene acts by a dual mechanism, which entails ERα antagonism and off-target mediators. Moreover, micromolar concentrations of Raloxifene increase the expression of immune metabolic genes, such as Vegfa and Hmox1, through PI3K and NRF2 activation selectively in peritoneal macrophages. Conversely, Il1b mRNA down-regulation by SERMs is consistently observed in all macrophage subtypes and unrelated to the PI3K/NRF2 system. Importantly, the production of the inflammatory cytokine TNFα induced by the bacterial endotoxin, LPS, is potentiated by SERMs and paralleled by the cell subtype-specific increase in IL1β secretion. This work extends our knowledge on the biological and molecular mechanisms of SERMs immune activity and indicate macrophages as a pharmacological target for the exploitation of the antimicrobial potential of these drugs.
MeSH term(s)	Mice ; Humans ; Animals ; Selective Estrogen Receptor Modulators/pharmacology ; Raloxifene Hydrochloride/pharmacology ; Estrogen Receptor alpha/genetics ; Estrogen Receptor alpha/metabolism ; Down-Regulation ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism ; Tamoxifen/pharmacology ; Macrophages/metabolism ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism
Chemical Substances	Selective Estrogen Receptor Modulators ; Raloxifene Hydrochloride (4F86W47BR6) ; Estrogen Receptor alpha ; NF-E2-Related Factor 2 ; Tamoxifen (094ZI81Y45) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-)
Language	English
Publishing date	2023-07-11
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2023.115008
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Article ; Online: ERα-Dependent Regulation of Adropin Predicts Sex Differences in Liver Homeostasis during High-Fat Diet.

Meda, Clara / Dolce, Arianna / Vegeto, Elisabetta / Maggi, Adriana / Della Torre, Sara

Nutrients

2022 Volume 14, Issue 16

Abstract: Non-alcoholic fatty liver disease (NAFLD) represents a public health issue, due to its prevalence and association with other cardiometabolic diseases. Growing evidence suggests that NAFLD alters the production of hepatokines, which, in turn, influence ... ...

Abstract	Non-alcoholic fatty liver disease (NAFLD) represents a public health issue, due to its prevalence and association with other cardiometabolic diseases. Growing evidence suggests that NAFLD alters the production of hepatokines, which, in turn, influence several metabolic processes. Despite accumulating evidence on the major role of estrogen signaling in the sexually dimorphic nature of NAFLD, dependency of hepatokine expression on sex and estrogens has been poorly investigated. Through in vitro and in vivo analysis, we determined the extent to which hepatokines, known to be altered in NAFLD, can be regulated, in a sex-specific fashion, under different hormonal and nutritional conditions. Our study identified four hepatokines that better recapitulate sex and estrogen dependency. Among them, adropin resulted as one that displays a sex-specific and estrogen receptor alpha (ERα)-dependent regulation in the liver of mice under an excess of dietary lipids (high-fat diet, HFD). Under HFD conditions, the hepatic induction of adropin negatively correlates with the expression of lipogenic genes and with fatty liver in female mice, an effect that depends upon hepatic ERα. Our findings support the idea that ERα-mediated induction of adropin might represent a potential approach to limit or prevent NAFLD.
MeSH term(s)	Animals ; Diet, High-Fat/adverse effects ; Estrogen Receptor alpha/genetics ; Estrogen Receptor alpha/metabolism ; Estrogens/genetics ; Estrogens/metabolism ; Female ; Homeostasis/genetics ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/metabolism ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease/etiology ; Non-alcoholic Fatty Liver Disease/genetics ; Non-alcoholic Fatty Liver Disease/metabolism
Chemical Substances	ESR1 protein, human ; Enho protein, human ; Estrogen Receptor alpha ; Estrogens ; Intercellular Signaling Peptides and Proteins
Language	English
Publishing date	2022-08-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu14163262
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Article: Tamoxifen Twists Again: On and Off-Targets in Macrophages and Infections.

Sfogliarini, Chiara / Pepe, Giovanna / Dolce, Arianna / Della Torre, Sara / Cesta, Maria Candida / Allegretti, Marcello / Locati, Massimo / Vegeto, Elisabetta

Frontiers in pharmacology

2022 Volume 13, Page(s) 879020

Abstract: Beyond the wide use of tamoxifen in breast cancer chemotherapy due to its estrogen receptor antagonist activity, this drug is being assayed in repurposing strategies against a number of microbial infections. We conducted a literature search on the ... ...

Abstract	Beyond the wide use of tamoxifen in breast cancer chemotherapy due to its estrogen receptor antagonist activity, this drug is being assayed in repurposing strategies against a number of microbial infections. We conducted a literature search on the evidence related with tamoxifen activity in macrophages, since these immune cells participate as a first line-defense against pathogen invasion. Consistent data indicate the existence of estrogen receptor-independent targets of tamoxifen in macrophages that include lipid mediators and signaling pathways, such as NRF2 and caspase-1, which allow these cells to undergo phenotypic adaptation and potentiate the inflammatory response, without the induction of cell death. Thus, these lines of evidence suggest that the widespread antimicrobial activity of this drug can be ascribed, at least in part, to the potentiation of the host innate immunity. This widens our understanding of the pharmacological activity of tamoxifen with relevant therapeutic implications for infections and other clinical indications that may benefit from the immunomodulatory effects of this drug.
Language	English
Publishing date	2022-03-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2022.879020
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Article: ERα-Dependent Regulation of Adropin Predicts Sex Differences in Liver Homeostasis during High-Fat Diet

Meda, Clara / Dolce, Arianna / Vegeto, Elisabetta / Maggi, Adriana / Della Torre, Sara

Nutrients. 2022 Aug. 10, v. 14, no. 16

2022

Abstract	Non-alcoholic fatty liver disease (NAFLD) represents a public health issue, due to its prevalence and association with other cardiometabolic diseases. Growing evidence suggests that NAFLD alters the production of hepatokines, which, in turn, influence several metabolic processes. Despite accumulating evidence on the major role of estrogen signaling in the sexually dimorphic nature of NAFLD, dependency of hepatokine expression on sex and estrogens has been poorly investigated. Through in vitro and in vivo analysis, we determined the extent to which hepatokines, known to be altered in NAFLD, can be regulated, in a sex-specific fashion, under different hormonal and nutritional conditions. Our study identified four hepatokines that better recapitulate sex and estrogen dependency. Among them, adropin resulted as one that displays a sex-specific and estrogen receptor alpha (ERα)-dependent regulation in the liver of mice under an excess of dietary lipids (high-fat diet, HFD). Under HFD conditions, the hepatic induction of adropin negatively correlates with the expression of lipogenic genes and with fatty liver in female mice, an effect that depends upon hepatic ERα. Our findings support the idea that ERα-mediated induction of adropin might represent a potential approach to limit or prevent NAFLD.
Keywords	estrogen receptors ; estrogens ; fatty liver ; females ; high fat diet ; homeostasis ; liver ; public health ; sexual dimorphism
Language	English
Dates of publication	2022-0810
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2518386-2
ISSN	2072-6643
ISSN	2072-6643
DOI	10.3390/nu14163262
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Inhibition of microglial β-glucocerebrosidase hampers the microglia-mediated antioxidant and protective response in neurons.

Brunialti, Electra / Villa, Alessandro / Mekhaeil, Marianna / Mornata, Federica / Vegeto, Elisabetta / Maggi, Adriana / Di Monte, Donato A / Ciana, Paolo

Journal of neuroinflammation

2021 Volume 18, Issue 1, Page(s) 220

Abstract: Background: Homozygotic mutations in the GBA gene cause Gaucher's disease; moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinson's disease. In homozygosis, these mutations ... ...

Abstract	Background: Homozygotic mutations in the GBA gene cause Gaucher's disease; moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinson's disease. In homozygosis, these mutations impair the activity of β-glucocerebrosidase, the enzyme encoded by GBA, and generate a lysosomal disorder in macrophages, which changes morphology towards an engorged phenotype, considered the hallmark of Gaucher's disease. Notwithstanding the key role of macrophages in this disease, most of the effects in the brain have been attributed to the β-glucocerebrosidase deficit in neurons, while a microglial phenotype for these mutations has never been reported. Methods: We applied the bioluminescence imaging technology, immunohistochemistry and gene expression analysis to investigate the consequences of microglial β-glucocerebrosidase inhibition in the brain of reporter mice, in primary neuron/microglia cocultures and in cell lines. The use of primary cells from reporter mice allowed for the first time, to discriminate in cocultures neuronal from microglial responses consequent to the β-glucocerebrosidase inhibition; results were finally confirmed by pharmacological depletion of microglia from the brain of mice. Results: Our data demonstrate the existence of a novel neuroprotective mechanism mediated by a direct microglia-to-neuron contact supported by functional actin structures. This cellular contact stimulates the nuclear factor erythroid 2-related factor 2 activity in neurons, a key signal involved in drug detoxification, redox balance, metabolism, autophagy, lysosomal biogenesis, mitochondrial dysfunctions, and neuroinflammation. The central role played by microglia in this neuronal response in vivo was proven by depletion of the lineage in the brain of reporter mice. Pharmacological inhibition of microglial β-glucocerebrosidase was proven to induce morphological changes, to turn on an anti-inflammatory/repairing pathway, and to hinder the microglia ability to activate the nuclear factor erythroid 2-related factor 2 response, thus increasing the neuronal susceptibility to neurotoxins. Conclusion: This mechanism provides a possible explanation for the increased risk of neurodegeneration observed in carriers of GBA mutations and suggest novel therapeutic strategies designed to revert the microglial phenotype associated with β-glucocerebrosidase inhibition, aimed at resetting the protective microglia-to-neuron communication.
MeSH term(s)	Animals ; Brain/enzymology ; Brain/pathology ; Cell Communication/physiology ; Glucosylceramidase/antagonists & inhibitors ; Mice ; Microglia/enzymology ; Microglia/pathology ; Neurons/metabolism ; Neurons/pathology ; Neuroprotection/physiology
Chemical Substances	Glucosylceramidase (EC 3.2.1.45)
Language	English
Publishing date	2021-09-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-021-02272-2
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Article ; Online: Estrogens, Neuroinflammation, and Neurodegeneration.

Villa, Alessandro / Vegeto, Elisabetta / Poletti, Angelo / Maggi, Adriana

Endocrine reviews

2016 Volume 37, Issue 4, Page(s) 372–402

Abstract: Inflammatory activation of microglia is a hallmark of several disorders of the central nervous system. In addition to protecting the brain against inflammatory insults, microglia are neuroprotective and play a significant role in maintaining neuronal ... ...

Abstract	Inflammatory activation of microglia is a hallmark of several disorders of the central nervous system. In addition to protecting the brain against inflammatory insults, microglia are neuroprotective and play a significant role in maintaining neuronal connectivity, but the prolongation of an inflammatory status may limit the beneficial functions of these immune cells. The finding that estrogen receptors are present in monocyte-derived cells and that estrogens prevent and control the inflammatory response raise the question of the role that this sex steroid plays in the manifestation and progression of pathologies that have a clear sex difference in prevalence, such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. The present review aims to provide a critical review of the current literature on the actions of estrogen in microglia and on the involvement of estrogen receptors in the manifestation of selected neurological disorders. This current understanding highlights a research area that should be expanded to identify appropriate replacement therapies to slow the progression of such diseases.
Language	English
Publishing date	2016-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	603096-8
ISSN	1945-7189 ; 0163-769X
ISSN (online)	1945-7189
ISSN	0163-769X
DOI	10.1210/er.2016-1007
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Article ; Online: Reciprocal interference between the NRF2 and LPS signaling pathways on the immune-metabolic phenotype of peritoneal macrophages.

Mornata, Federica / Pepe, Giovanna / Sfogliarini, Chiara / Brunialti, Electra / Rovati, Gianenrico / Locati, Massimo / Maggi, Adriana / Vegeto, Elisabetta

Pharmacology research & perspectives

2020 Volume 8, Issue 4, Page(s) e00638

Abstract: The metabolic and immune adaptation to extracellular signals allows macrophages to carry out specialized functions involved in immune protection and tissue homeostasis. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that ... ...

Abstract	The metabolic and immune adaptation to extracellular signals allows macrophages to carry out specialized functions involved in immune protection and tissue homeostasis. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that coordinates cell redox and metabolic responses to stressors. However, the individual and concomitant activation of NRF2 and inflammatory pathways have been poorly investigated in isolated macrophages. We here took advantage of reporter mice for the transcriptional activities of NRF2 and nuclear factor-kB (NFκB), a key transcription factor in inflammation, and observe a persisting reciprocal interference in the response of peritoneal macrophages to the respective activators, tert-Butylhydroquinone (tBHQ) and lipopolysaccharide (LPS). When analyzed separately by gene expression studies, these pathways trigger macrophage-specific metabolic and proliferative target genes that are associated with tBHQ-induced pentose phosphate pathway (PPP) with no proliferative response, and with opposite effects observed with LPS. Importantly, the simultaneous administration of tBHQ + LPS alters the effects of each individual pathway in a target gene-specific manner. In fact, this co-treatment potentiates the effects of tBHQ on the antioxidant enzyme, HMOX1, and the antibacterial enzyme, IRG1, respectively; moreover, the combined treatment reduces tBHQ activity on the glycolytic enzymes, TALDO1 and TKT, and decreases LPS effects on the metabolic enzyme IDH1, the proliferation-related proteins KI67 and PPAT, and the inflammatory cytokines IL-1β, IL-6, and TNFα. Altogether, our results show that the activation of NRF2 redirects the metabolic, immune, and proliferative response of peritoneal macrophages to inflammatory signals, with relevant consequences for the pharmacological treatment of diseases that are associated with unopposed inflammatory responses.
MeSH term(s)	Animals ; Cell Proliferation/physiology ; Cytokines/immunology ; Female ; Genes, Reporter ; Hydroquinones/toxicity ; Inflammation/immunology ; Inflammation/pathology ; Lipopolysaccharides/toxicity ; Macrophages, Peritoneal/immunology ; Macrophages, Peritoneal/pathology ; Mice ; Mice, Inbred C57BL ; NF-E2-Related Factor 2/genetics ; NF-kappa B/genetics ; Signal Transduction/immunology
Chemical Substances	Cytokines ; Hydroquinones ; Lipopolysaccharides ; NF-E2-Related Factor 2 ; NF-kappa B ; Nfe2l2 protein, mouse ; 2-tert-butylhydroquinone (C12674942B)
Language	English
Publishing date	2020-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2740389-0
ISSN	2052-1707 ; 2052-1707
ISSN (online)	2052-1707
ISSN	2052-1707
DOI	10.1002/prp2.638
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Article ; Online: ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen.

Pepe, Giovanna / Sfogliarini, Chiara / Rizzello, Loris / Battaglia, Giuseppe / Pinna, Christian / Rovati, Gianenrico / Ciana, Paolo / Brunialti, Electra / Mornata, Federica / Maggi, Adriana / Locati, Massimo / Vegeto, Elisabetta

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2021 Volume 144, Page(s) 112274

Abstract: 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 ... ...

Abstract	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. Altogether, our data unravel a novel molecular mechanism and immune functions for TAM and 4HT, sustaining their repurposing in infective and other estrogen receptors-unrelated pathologies.
MeSH term(s)	Animals ; Cells, Cultured ; Estrogen Receptor alpha/genetics ; Estrogen Receptor alpha/metabolism ; Female ; Immunomodulating Agents/pharmacology ; Inflammation Mediators/metabolism ; Lipopolysaccharides/pharmacology ; Macrophages, Peritoneal/drug effects ; Macrophages, Peritoneal/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; NF-E2-Related Factor 2/metabolism ; Phagocytosis/drug effects ; Phenotype ; Receptors, Estrogen/metabolism ; Receptors, G-Protein-Coupled/metabolism ; Selective Estrogen Receptor Modulators/pharmacology ; Signal Transduction ; Tamoxifen/analogs & derivatives ; Tamoxifen/pharmacology ; Mice
Chemical Substances	Esr1 protein, mouse ; Estrogen Receptor alpha ; GPER1 protein, mouse ; Immunomodulating Agents ; Inflammation Mediators ; Lipopolysaccharides ; NF-E2-Related Factor 2 ; Nfe2l2 protein, mouse ; Receptors, Estrogen ; Receptors, G-Protein-Coupled ; Selective Estrogen Receptor Modulators ; lipopolysaccharide, Escherichia coli O111 B4 ; Tamoxifen (094ZI81Y45) ; afimoxifene (17197F0KYM)
Language	English
Publishing date	2021-10-12
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2021.112274
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