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Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells

There is a growing appreciation that a tight relationship exists between cholesterol homeostasis and immunity in leukocytes; however, this relationship has not been deeply explored in the vascular endothelium. Endothelial cells (ECs) rapidly respond to extrinsic signals, such as tissue damage or mic...

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Autores principales: Fowler, Joseph Wayne M, Zhang, Rong, Tao, Bo, Boutagy, Nabil E, Sessa, William C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9395194/
https://www.ncbi.nlm.nih.gov/pubmed/35959888
http://dx.doi.org/10.7554/eLife.79529
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author Fowler, Joseph Wayne M
Zhang, Rong
Tao, Bo
Boutagy, Nabil E
Sessa, William C
author_facet Fowler, Joseph Wayne M
Zhang, Rong
Tao, Bo
Boutagy, Nabil E
Sessa, William C
author_sort Fowler, Joseph Wayne M
collection PubMed
description There is a growing appreciation that a tight relationship exists between cholesterol homeostasis and immunity in leukocytes; however, this relationship has not been deeply explored in the vascular endothelium. Endothelial cells (ECs) rapidly respond to extrinsic signals, such as tissue damage or microbial infection, by upregulating factors to activate and recruit circulating leukocytes to the site of injury and aberrant activation of ECs leads to inflammatory based diseases, such as multiple sclerosis and atherosclerosis. Here, we studied the role of cholesterol and a key transcription regulator of cholesterol homeostasis, SREBP2, in the EC responses to inflammatory stress. Treatment of primary human ECs with pro-inflammatory cytokines upregulated SREBP2 cleavage and cholesterol biosynthetic gene expression within the late phase of the acute inflammatory response. Furthermore, SREBP2 activation was dependent on NF-κB DNA binding and canonical SCAP-SREBP2 processing. Mechanistically, inflammatory activation of SREBP was mediated by a reduction in accessible cholesterol, leading to heightened sterol sensing and downstream SREBP2 cleavage. Detailed analysis of NF-κB inducible genes that may impact sterol sensing resulted in the identification of a novel RELA-inducible target, STARD10, that mediates accessible cholesterol homeostasis in ECs. Thus, this study provides an in-depth characterization of the relationship between cholesterol homeostasis and the acute inflammatory response in EC.
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spelling pubmed-93951942022-08-23 Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells Fowler, Joseph Wayne M Zhang, Rong Tao, Bo Boutagy, Nabil E Sessa, William C eLife Immunology and Inflammation There is a growing appreciation that a tight relationship exists between cholesterol homeostasis and immunity in leukocytes; however, this relationship has not been deeply explored in the vascular endothelium. Endothelial cells (ECs) rapidly respond to extrinsic signals, such as tissue damage or microbial infection, by upregulating factors to activate and recruit circulating leukocytes to the site of injury and aberrant activation of ECs leads to inflammatory based diseases, such as multiple sclerosis and atherosclerosis. Here, we studied the role of cholesterol and a key transcription regulator of cholesterol homeostasis, SREBP2, in the EC responses to inflammatory stress. Treatment of primary human ECs with pro-inflammatory cytokines upregulated SREBP2 cleavage and cholesterol biosynthetic gene expression within the late phase of the acute inflammatory response. Furthermore, SREBP2 activation was dependent on NF-κB DNA binding and canonical SCAP-SREBP2 processing. Mechanistically, inflammatory activation of SREBP was mediated by a reduction in accessible cholesterol, leading to heightened sterol sensing and downstream SREBP2 cleavage. Detailed analysis of NF-κB inducible genes that may impact sterol sensing resulted in the identification of a novel RELA-inducible target, STARD10, that mediates accessible cholesterol homeostasis in ECs. Thus, this study provides an in-depth characterization of the relationship between cholesterol homeostasis and the acute inflammatory response in EC. eLife Sciences Publications, Ltd 2022-08-12 /pmc/articles/PMC9395194/ /pubmed/35959888 http://dx.doi.org/10.7554/eLife.79529 Text en © 2022, Fowler et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Immunology and Inflammation
Fowler, Joseph Wayne M
Zhang, Rong
Tao, Bo
Boutagy, Nabil E
Sessa, William C
Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells
title Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells
title_full Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells
title_fullStr Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells
title_full_unstemmed Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells
title_short Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells
title_sort inflammatory stress signaling via nf-kb alters accessible cholesterol to upregulate srebp2 transcriptional activity in endothelial cells
topic Immunology and Inflammation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9395194/
https://www.ncbi.nlm.nih.gov/pubmed/35959888
http://dx.doi.org/10.7554/eLife.79529
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