REELIN – A NOVEL TARGET FOR THE PREVENTION OF INFLAMMATORY DISEASE
Cell Biology
Final Report Abstract
Multiple sclerosis (MS) is a chronic inflammation of the central nervous system relying on recruitment of circulating immune cells. Therefore, all current therapeutic approaches to MS target the immune system, blocking inflammation and paralysis progression. We have developed a mechanistically different therapeutic approach by selectively targeting endothelial permeability to block neuroinflammation and MS progression by preventing monocyte extravasation to the central nervous system. To support this conceptually novel approach, we present data using an in vitro human system, as well as four in vivo mouse models. The main findings reported in this project are: Human plasma Reelin functions as an ApoER2/NF-κB activator and promotes monocyte adhesion to endothelial cells. This is inhibited by a Reelin blocking antibody. - In mice, genetic or pharmacologic (antibody-mediated) depletion of Reelin reduces the expression of adhesion markers on endothelial cells, thus reducing monocyte adhesion to the vascular wall. - Consequently, in a MS mouse model, both genetic and pharmacologic Reelin depletion reduces monocyte extravasation, preventing neuroinflammation, demyelination, and ultimately paralysis progression. This novel therapeutic approach opens the door to other clinical applications in chronic inflammatory diseases beyond MS, e.g. arthritis, atherosclerosis, Crohn’s disease, and others.
Publications
- (2020) Reelin depletion protects against autoimmune encephalomyelitis by decreasing vascular adhesion of leukocytes. Science translational medicine 12 (556) 36-47
Calvier, Laurent; Demuth, Guillaume; Manouchehri, Navid; Wong, Connie; Sacharidou, Anastasia; Mineo, Chieko; Shaul, Philip W.; Monson, Nancy L.; Kounnas, Maria Z.; Stüve, Olaf; Herz, Joachim
(See online at https://doi.org/10.1126/scitranslmed.aay7675)
