Notch signalling in inflammation

The vascular endothelium is the thin layer of cells that lines the interior surface of all blood vessels. These cells regulate the migration of white blood cells out from blood vessels to the tissues during inflammation. Today, millions of people worldwide suffer from inflammatory diseases, and many do not respond appropriately to current treatment options. Thus, there is a need for new and better anti-inflammatory medicines. Recent evidence reveals that the Notch pathway, a cell-to-cell signaling system first described almost 100 years ago, is involved in regulating inflammation. This project was designed to understand how the Notch pathway affects activation of the vascular endothelium and modulates the inflammatory response. It also aimed to assess whether global Notch inhibition by means of blocking antibodies is a potential treatment modality for inflammatory diseases. Considerable progress in our understanding of Notch signaling during inflammation has been made. The CIA rheumatoid arthritis model has been established in our lab and to date, several experiments have been implemented. Unfortunately, results do not indicate that blocking individual Notch ligands or receptors alleviates arthritis in this model. However, project manager and ophthalmologist Eirik Sundlisæter established the laser-induced CNV model as planned and results are encouraging. By blocking one of the Notch ligand, choroidal neovascularization is ameliorated. We have also been successful in financing a brand new, advanced retinal microscope with integrated laser with funding from UiO. The equipment was successfully installed at Rikshospitalet in April 2018 and is a great leap forward for experimental eye research in Norway. The mechanisms behind the positive effect observed seems to be VEGF independent and may thus represent a novel therapeutic target. The article "Inhibition of endothelial NOTCH1 signaling attenuates inflammation by reducing cytokine-mediated histone acetylation at inflammatory enhancers" was published in ATVB in 2018. The article "Antiangiogenic treatment of ocular diseases" was published november 2018. Moreover, an article on anti-VEGF treatment of AMD was also recently accepted for publikcation Oftalmolog. 2 manuscripts, including one review, is ready for submission.

Publiserte og fremtidig publiserte arbeider tilfører ny vitenskapelig innsikt. Potensielle virkninger og effekter av prosjektets resultater er utvikling av et nytt legemiddel til behandling av neovaskulære øyesykdommer som våt AMD, diabetisk retinopati, retinale veneokklusjoner og retinopati hos premature.

Vascular endothelial cells are central players in the initiation and amplification of inflammatory responses, and their role in recruiting leukocytes to inflammatory lesions is now well characterized. Recent evidence reveals that the Notch pathway is involved in regulating inflammation. This is not entirely surprizing, because the Notch signalling system has been found to interact with the NF-kB pathway and therefore potentially interfere with the action of pro-inflammatory cytokines such as TNF-alpha and IL-1beta, as well as TLR agonists. Indeed, inhibition of Notch signalling ameliorates experimental arthritis, acute colitis, acute lung injury and graft-versus-host disease. On the other hand, inhibition of Notch signalling may also reduce the epidermal barrier function, leading to atopic dermatitis. At the cellular level of inflammation, Notch signalling affects the effector function of mast cells and T cells as well as the proinflammatory activation of synoviocytes. By contrast, the role of Notch signalling in endothelial cells in the context of inflammatory function such as leukocyte recruitment was not been explored until recently. Here we propose experiments that build on recent breakthroughs in our lab and the inclusion/generation of novel model systems. This project is designed to further understand how the Notch signalling system affects endothelial activation and modulates the inflammatory response. Perhaps more important, it also aims to assess whether global Notch inhibiton by means of blocking antibodies is a potential treatment modality for inflammatory diseases. These experiments are based on our recent discovery that the Notch ligand Jagged1 promotes the pro-inflammatory activation of vascular endothelial cells and in vivo experiments on endothelial-specific, tamoxifen-inducible knock-out and knock-in mice showing that Notch inhibition reduces inflammation in contact dermatitis.