Inhibition of mevalonate metabolism by statins augments the immunoregulatory phenotype of vascular endothelial cells and inhibits the costimulation of CD4+ T cells

The statin family of therapeutics is widely used clinically as cholesterol lowering agents, and their effects to target intracellular mevalonate production is a key mechanism of action. In this study, we performed full transcriptomic RNA sequencing and qPCR to evaluate the effects of mevalonate on t...

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Veröffentlicht in:	American journal of transplantation Jg. 22; H. 3; S. 947 - 954
Hauptverfasser:	Agur, Timna, Wedel, Johannes, Bose, Sayantan, Sahankumari, A. G. Pramoda, Goodman, Daniel, Kong, Sek Won, Ghosh, Chandra C., Briscoe, David M.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Elsevier Limited 01.03.2022
Schlagworte:	basic (laboratory) research/science CD4 antigen CD4-Positive T-Lymphocytes - metabolism Cell proliferation Cells, Cultured Cholesterol Endothelial Cells Gene regulation Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology immune regulation immunobiology Immunoregulation Inflammation Lymphocytes T Metabolism Mevalonic acid Mevalonic Acid - metabolism Mevalonic Acid - pharmacology Phenotype Phenotypes Simvastatin Simvastatin - pharmacology Statins T-Lymphocytes - metabolism Transcriptomics Transplantation Tumor necrosis factor vascular biology γ-Interferon immunobiology vascular biology immune regulation basic (laboratory) research/science
ISSN:	1600-6135, 1600-6143, 1600-6143
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Abstract	The statin family of therapeutics is widely used clinically as cholesterol lowering agents, and their effects to target intracellular mevalonate production is a key mechanism of action. In this study, we performed full transcriptomic RNA sequencing and qPCR to evaluate the effects of mevalonate on the immunoregulatory phenotype of endothelial cells (EC). We find that mevalonate‐dependent gene regulation includes a reduction in the expression of multiple pro‐inflammatory genes including TNFSF4 (OX40‐L) and TNFSF18 (GITR‐L) and a co‐incident induction of immunoregulatory genes including LGALS3 (Galectin‐3) and LGALS9 (Galectin‐9). In functional assays, pretreatment of EC with simvastatin to inhibit mevalonate metabolism resulted in a dose‐dependent reduction in the costimulation of CD45RO+CD4+ T cell proliferation as well as IL‐2, IFNγ and IL‐6 production versus vehicle‐treated EC. In contrast, pre‐treatment of EC with L‐mevalonate in combination with simvastatin reversed phenotypic and functional responses. Collectively, these results indicate that relative mevalonate metabolism by EC is critical to sustain EC‐dependent mechanisms of immunity. Our findings have broad relevance for the repurposing of statins as therapeutics to augment immunoregulation and/or to inhibit local tissue pro‐inflammatory cytokine production following transplantation. Treatment of endothelial cells with statins is associated with reduced expression of pro‐inflammatory genes, induced expression of immunoregulatory genes and a dose‐dependent inhibition in the costimulation of CD4+CD45RO+ memory T cell proliferation and cytokine production.
AbstractList	The statin family of therapeutics is widely used clinically as cholesterol lowering agents, and their effects to target intracellular mevalonate production is a key mechanism of action. In this study, we performed full transcriptomic RNA sequencing and qPCR to evaluate the effects of mevalonate on the immunoregulatory phenotype of endothelial cells (EC). We find that mevalonate-dependent gene regulation includes a reduction in the expression of multiple pro-inflammatory genes including TNFSF4 (OX40-L) and TNFSF18 (GITR-L) and a co-incident induction of immunoregulatory genes including LGALS3 (Galectin-3) and LGALS9 (Galectin-9). In functional assays, pretreatment of EC with simvastatin to inhibit mevalonate metabolism resulted in a dose-dependent reduction in the costimulation of CD45RO+ CD4+ T cell proliferation as well as IL-2, IFNγ and IL-6 production versus vehicle-treated EC. In contrast, pre-treatment of EC with L-mevalonate in combination with simvastatin reversed phenotypic and functional responses. Collectively, these results indicate that relative mevalonate metabolism by EC is critical to sustain EC-dependent mechanisms of immunity. Our findings have broad relevance for the repurposing of statins as therapeutics to augment immunoregulation and/or to inhibit local tissue pro-inflammatory cytokine production following transplantation.The statin family of therapeutics is widely used clinically as cholesterol lowering agents, and their effects to target intracellular mevalonate production is a key mechanism of action. In this study, we performed full transcriptomic RNA sequencing and qPCR to evaluate the effects of mevalonate on the immunoregulatory phenotype of endothelial cells (EC). We find that mevalonate-dependent gene regulation includes a reduction in the expression of multiple pro-inflammatory genes including TNFSF4 (OX40-L) and TNFSF18 (GITR-L) and a co-incident induction of immunoregulatory genes including LGALS3 (Galectin-3) and LGALS9 (Galectin-9). In functional assays, pretreatment of EC with simvastatin to inhibit mevalonate metabolism resulted in a dose-dependent reduction in the costimulation of CD45RO+ CD4+ T cell proliferation as well as IL-2, IFNγ and IL-6 production versus vehicle-treated EC. In contrast, pre-treatment of EC with L-mevalonate in combination with simvastatin reversed phenotypic and functional responses. Collectively, these results indicate that relative mevalonate metabolism by EC is critical to sustain EC-dependent mechanisms of immunity. Our findings have broad relevance for the repurposing of statins as therapeutics to augment immunoregulation and/or to inhibit local tissue pro-inflammatory cytokine production following transplantation. The statin family of therapeutics is widely used clinically as cholesterol lowering agents, and their effects to target intracellular mevalonate production is a key mechanism of action. In this study, we performed full transcriptomic RNA sequencing and qPCR to evaluate the effects of mevalonate on the immunoregulatory phenotype of endothelial cells (EC). We find that mevalonate‐dependent gene regulation includes a reduction in the expression of multiple pro‐inflammatory genes including TNFSF4 (OX40‐L) and TNFSF18 (GITR‐L) and a co‐incident induction of immunoregulatory genes including LGALS3 (Galectin‐3) and LGALS9 (Galectin‐9). In functional assays, pretreatment of EC with simvastatin to inhibit mevalonate metabolism resulted in a dose‐dependent reduction in the costimulation of CD45RO+CD4+ T cell proliferation as well as IL‐2, IFNγ and IL‐6 production versus vehicle‐treated EC. In contrast, pre‐treatment of EC with L‐mevalonate in combination with simvastatin reversed phenotypic and functional responses. Collectively, these results indicate that relative mevalonate metabolism by EC is critical to sustain EC‐dependent mechanisms of immunity. Our findings have broad relevance for the repurposing of statins as therapeutics to augment immunoregulation and/or to inhibit local tissue pro‐inflammatory cytokine production following transplantation. Treatment of endothelial cells with statins is associated with reduced expression of pro‐inflammatory genes, induced expression of immunoregulatory genes and a dose‐dependent inhibition in the costimulation of CD4+CD45RO+ memory T cell proliferation and cytokine production. The statin family of therapeutics is widely used clinically as cholesterol lowering agents, and their effects to target intracellular mevalonate production is a key mechanism of action. In this study, we performed full transcriptomic RNA sequencing and qPCR to evaluate the effects of mevalonate on the immunoregulatory phenotype of endothelial cells (EC). We find that mevalonate-dependent gene regulation includes a reduction in the expression of multiple pro-inflammatory genes including TNFSF4 (OX40-L) and TNFSF18 (GITR-L) and a co-incident induction of immunoregulatory genes including LGALS3 (Galectin-3) and LGALS9 (Galectin-9). In functional assays, pretreatment of EC with simvastatin to inhibit mevalonate metabolism resulted in a dose-dependent reduction in the costimulation of CD45RO CD4 T cell proliferation as well as IL-2, IFNγ and IL-6 production versus vehicle-treated EC. In contrast, pre-treatment of EC with L-mevalonate in combination with simvastatin reversed phenotypic and functional responses. Collectively, these results indicate that relative mevalonate metabolism by EC is critical to sustain EC-dependent mechanisms of immunity. Our findings have broad relevance for the repurposing of statins as therapeutics to augment immunoregulation and/or to inhibit local tissue pro-inflammatory cytokine production following transplantation. The statin family of therapeutics is widely used clinically as cholesterol lowering agents, and their effects to target intracellular mevalonate production is a key mechanism of action. In this study, we performed full transcriptomic RNA sequencing and qPCR to evaluate the effects of mevalonate on the immunoregulatory phenotype of endothelial cells (EC). We find that mevalonate‐dependent gene regulation includes a reduction in the expression of multiple pro‐inflammatory genes including TNFSF4 (OX40‐L) and TNFSF18 (GITR‐L) and a co‐incident induction of immunoregulatory genes including LGALS3 (Galectin‐3) and LGALS9 (Galectin‐9). In functional assays, pretreatment of EC with simvastatin to inhibit mevalonate metabolism resulted in a dose‐dependent reduction in the costimulation of CD45RO+CD4+ T cell proliferation as well as IL‐2, IFNγ and IL‐6 production versus vehicle‐treated EC. In contrast, pre‐treatment of EC with L‐mevalonate in combination with simvastatin reversed phenotypic and functional responses. Collectively, these results indicate that relative mevalonate metabolism by EC is critical to sustain EC‐dependent mechanisms of immunity. Our findings have broad relevance for the repurposing of statins as therapeutics to augment immunoregulation and/or to inhibit local tissue pro‐inflammatory cytokine production following transplantation.
Author	Wedel, Johannes Goodman, Daniel Ghosh, Chandra C. Briscoe, David M. Bose, Sayantan Sahankumari, A. G. Pramoda Kong, Sek Won Agur, Timna
Author_xml	– sequence: 1 givenname: Timna orcidid: 0000-0001-8263-0900 surname: Agur fullname: Agur, Timna organization: Department of Pediatrics, Harvard Medical School – sequence: 2 givenname: Johannes orcidid: 0000-0002-3490-8477 surname: Wedel fullname: Wedel, Johannes organization: Department of Pediatrics, Harvard Medical School – sequence: 3 givenname: Sayantan orcidid: 0000-0001-6413-2019 surname: Bose fullname: Bose, Sayantan organization: Department of Pediatrics, Harvard Medical School – sequence: 4 givenname: A. G. Pramoda orcidid: 0000-0002-9201-5562 surname: Sahankumari fullname: Sahankumari, A. G. Pramoda organization: Boston Children’s Hospital – sequence: 5 givenname: Daniel surname: Goodman fullname: Goodman, Daniel organization: Boston Children’s Hospital – sequence: 6 givenname: Sek Won orcidid: 0000-0003-4877-7567 surname: Kong fullname: Kong, Sek Won organization: Department of Pediatrics, Harvard Medical School – sequence: 7 givenname: Chandra C. surname: Ghosh fullname: Ghosh, Chandra C. organization: Department of Pediatrics, Harvard Medical School – sequence: 8 givenname: David M. orcidid: 0000-0003-4135-5417 surname: Briscoe fullname: Briscoe, David M. email: david.briscoe@childrens.harvard.edu organization: Department of Pediatrics, Harvard Medical School
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Notes	Chandra C. Ghosh and David M. Briscoe served as co‐senior authors. Timna Agur and Johannes Wedel contributed equally as first authors. This work was supported by Isabella Julian Forrest Foundation (to DMB) and by a travel fellowship award from the Rabin Medical Center, Israel (to TA). ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
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Snippet	The statin family of therapeutics is widely used clinically as cholesterol lowering agents, and their effects to target intracellular mevalonate production is...
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SubjectTerms	basic (laboratory) research/science CD4 antigen CD4-Positive T-Lymphocytes - metabolism Cell proliferation Cells, Cultured Cholesterol Endothelial Cells Gene regulation Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology immune regulation immunobiology Immunoregulation Inflammation Lymphocytes T Metabolism Mevalonic acid Mevalonic Acid - metabolism Mevalonic Acid - pharmacology Phenotype Phenotypes Simvastatin Simvastatin - pharmacology Statins T-Lymphocytes - metabolism Transcriptomics Transplantation Tumor necrosis factor vascular biology γ-Interferon
Title	Inhibition of mevalonate metabolism by statins augments the immunoregulatory phenotype of vascular endothelial cells and inhibits the costimulation of CD4+ T cells
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