Inhibition of Endothelial NOTCH1 Signaling Attenuates Inflammation by Reducing Cytokine-Mediated Histone Acetylation at Inflammatory Enhancers.

Abstract

OBJECTIVE:

Endothelial upregulation of adhesion molecules serves to recruit leukocytes to inflammatory sites and appears to be promoted by NOTCH1; however, current models based on interactions between active NOTCH1 and NF-κB components cannot explain the transcriptional selectivity exerted by NOTCH1 in this context.

APPROACH AND RESULTS:

Observing that Cre/Lox-induced conditional mutations of endothelial Notch modulated inflammation in murine contact hypersensitivity, we found that IL (interleukin)-1β stimulation induced rapid recruitment of RELA (v-rel avian reticuloendotheliosis viral oncogene homolog A) to genomic sites occupied by NOTCH1-RBPJ (recombination signal-binding protein for immunoglobulin kappa J region) and that NOTCH1 knockdown reduced histone H3K27 acetylation at a subset of NF-κB-directed inflammatory enhancers.

CONCLUSIONS:

Our findings reveal that NOTCH1 signaling supports the expression of a subset of inflammatory genes at the enhancer level and demonstrate how key signaling pathways converge on chromatin to coordinate the transition to an infla mmatory endothelial phenotype.

• Authors: Lars la Cour Poulsen, Reidunn Jetne Edelmann, Stig Krüger, Rodrigo Diéguez-Hurtado, Akshay Shah, Tor Espen Stav-Noraas, Anastasia Renzi, Monika Szymanska, Junbai Wang, Manuel Ehling, Rui Benedito, Monika Kasprzycka, Espen Bækkevold, Olav Sundnes, Kim S Midwood, Helge Scott, Philippe Collas, Christian W Siebel, Ralf H Adams, Guttorm Haraldsen, Eirik Sundlisæter, Johanna Hol
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 38 Issue 4 Pg. 854-869 (04 2018) ISSN: 1524-4636 [Electronic] United States
• PMID: 29449332 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 American Heart Association, Inc.

Chemical References

• Dipeptides
• Histones
• Immunoglobulin J Recombination Signal Sequence-Binding Protein
• Interleukin-1beta
• N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
• NOTCH1 protein, human
• Notch1 protein, mouse
• Rbpj protein, mouse
• Receptor, Notch1
• Rela protein, mouse
• Transcription Factor RelA

Topics

• Acetylation
• Animals
• Appendicitis (metabolism, pathology)
• Cells, Cultured
• Dermatitis, Contact (genetics, metabolism, pathology)
• Dipeptides (pharmacology)
• Disease Models, Animal
• Endothelial Cells (drug effects, metabolism, pathology)
• Female
• Gene Expression Regulation (drug effects)
• Histones (metabolism)
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism, pathology)
• Humans
• Immunoglobulin J Recombination Signal Sequence-Binding Protein (genetics, metabolism)
• Inflammation (genetics, metabolism, pathology, prevention & control)
• Interleukin-1beta (pharmacology)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Phenotype
• Receptor, Notch1 (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)
• Transcription Factor RelA (genetics, metabolism)