LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux

• Published in: Cell reports (Cambridge) 2018-12, Vol.25 (13), p.3774-3785.e4
• Main Authors: Thomas, David G., Doran, Amanda C., Fotakis, Panagiotis, Westerterp, Marit, Antonson, Per, Jiang, Hui, Jiang, Xian-Cheng, Gustafsson, Jan-Åke, Tabas, Ira, Tall, Alan R.
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Biological Transport; Cell Movement - genetics; Cell- och molekylärbiologi; cholesterol; Cholesterol - metabolism; cholesterol efflux; Chromatin - metabolism; cis-repression; Enhancer Elements, Genetic - genetics; Female; Gene Expression Regulation; Inflammation - genetics; Inflammation - pathology; liver X receptor; Liver X Receptors - agonists; Liver X Receptors - metabolism; LXR; Medicin och hälsovetenskap; Medicinsk bioteknologi; Medicinsk bioteknologi (inriktn. mot cellbiologi (inkl. stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci); Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Mice, Inbred C57BL; neutrophil migration; Neutrophils - metabolism; Neutrophils - pathology; nuclear receptor; oxysterol; peritonitis; transrepression
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.11.100

The activation of liver X receptor (LXR) promotes cholesterol efflux and repression of inflammatory genes with anti-atherogenic consequences. The mechanisms underlying the repressive activity of LXR are controversial and have been attributed to cholesterol efflux or to transrepression of activator protein-1 (AP-1) activity. Here, we find that cholesterol efflux contributes to LXR repression, while the direct repressive functions of LXR also play a key role but are independent of AP-1. We use assay for transposase-accessible chromatin using sequencing (ATAC-seq) to show that LXR reduces chromatin accessibility in cis at inflammatory gene enhancers containing LXR binding sites. Targets of this repressive activity are associated with leukocyte adhesion and neutrophil migration, and LXR agonist treatment suppresses neutrophil recruitment in a mouse model of sterile peritonitis. These studies suggest a model of repression in which liganded LXR binds in cis to canonical nuclear receptor binding sites and represses pro-atherogenic leukocyte functions in tandem with the induction of LXR targets mediating cholesterol efflux. [Display omitted] •Cholesterol efflux and direct repression mediate LXR’s anti-inflammatory effects•LXR cis-repression involves direct binding of LXR to inflammatory gene enhancers•LXR agonist treatment suppresses neutrophil recruitment during inflammation•Targets of LXR repression are involved in neutrophil migration Thomas et al. show the roles of cholesterol efflux and direct repression in anti-inflammatory effects of LXR and establish the mechanism of LXR cis-repression using ATAC-seq. LXR agonists suppress neutrophil migration genes and neutrophil recruitment during inflammation, highlighting a potential role for these compounds in the control of neutrophil-predominant inflammatory conditions.