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 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-kB 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-kB 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.
Sequencing data have been deposited in GEO under accession code GSE201466.All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for all figures.
Article and author information
- William C Sessa
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All animals were handed according to approved institutional animal care and use committee (IACUC) protocols (#07919-2020) of Yale University.
- Edward A Fisher, New York University Grossman School of Medicine, United States
- Received: April 15, 2022
- Preprint posted: May 5, 2022 (view preprint)
- Accepted: August 11, 2022
- Accepted Manuscript published: August 12, 2022 (version 1)
- Version of Record published: August 22, 2022 (version 2)
© 2022, Fowler et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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