Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells.
Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells.
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DOI：
10.7554/elife.79529
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发表时间：
2022-08-12
期刊：
影响因子：
7.7
通讯作者：
Sessa, William C.
中科院分区：
文献类型：
--
作者：
Fowler, Joseph Wayne M.;Zhang, Rong;Tao, Bo;Boutagy, Nabil E.;Sessa, William C.
越来越多的人认识到，白细胞中胆固醇稳态和免疫力之间存在紧密的关系;然而，这种关系在血管内皮中尚未深入研究。内皮细胞（EC）通过上调因子以激活和募集循环白细胞至损伤部位而快速响应于外部信号，诸如组织损伤或微生物感染，并且EC的异常激活导致基于炎症的疾病，诸如多发性硬化和动脉粥样硬化。在这里，我们研究了胆固醇和胆固醇稳态的关键转录调节因子SREBP 2在EC对炎症应激反应中的作用。用促炎细胞因子处理原代人EC在急性炎症反应的晚期上调SREBP 2裂解和胆固醇生物合成基因表达。此外，SREBP 2的激活依赖于NF-κB DNA结合和典型的SCAP-SREBP 2加工。从机制上讲，SREBP的炎性激活是由可接近胆固醇的减少介导的，从而导致甾醇敏感性提高和下游SREBP 2裂解。对可能影响固醇感知的NF-κB诱导型基因的详细分析导致鉴定了新的RELA诱导型靶点STARD 10，其介导EC中可接近的胆固醇稳态。因此，本研究深入描述了EC中胆固醇稳态与急性炎症反应之间的关系。
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.