Targeting endothelial dysfunction to stop the infiltration of inflammatory cells in inflammatory diseases, with a special focus on the Reelin protein.
Background.
Chronic inflammatory diseases, including autoimmune conditions like multiple sclerosis (MS), are marked by persistent low-grade inflammation. Current drugs typically target the immune system to halt inflammation but often lead to immunosuppressive side effects, highlighting the need for alternative strategies. To this end, we have studied a newly discovered endothelial factor, Reelin, known for its role in neuronal guidance and function in the brain, but previously overlooked in peripheral functions.
Main results.
In our most recent research, we demonstrated that Reelin is abundant in the circulation where it correlates with inflammatory disease severity, such as MS, atherosclerosis, or COVID-19. This circulating protein promotes endothelial dysfunction by increasing adhesion and permeability properties to leukocytes, thus propagating inflammation. Mechanistically, we established in endothelial cells that circulating Reelin binds to ApoER2 to activate the NF-κB signaling pathway, thus promoting the expression of adhesion proteins on the endothelial surface. These results have far-reaching applications in chronic inflammatory diseases, where Reelin therapeutic inhibition restores the endothelial barrier function, thus decreasing inflammation. Consequently, Reelin inhibition in mouse models prevented plaque formation in atherosclerosis, paralysis in MS, and death in COVID-19.
Impact.
Innovative approaches to address chronic neuroinflammation are crucial, considering the immunosuppressive side effects associated with current anti-inflammatory MS drugs. Instead of targeting the immune system, our research differentiates by focusing on leveraging the pivotal role of the blood-brain barrier (BBB) in neuroinflammation, utilizing circulating Reelin to restore BBB integrity. The pre-clinical application of anti-Reelin therapies, featured in several widely accessible webzines, has generated significant interest and transcended academic circles, with patients expressing a keen interest in participating in forthcoming clinical studies. To advance these promising outcomes, we have patented the research and co-founded Reelin Therapeutics, Inc. The company aims to develop a Reelin-specific ELISA for clinical use, facilitating patient stratification for anti-Reelin therapy, and is actively working on anti-Reelin treatment for treating chronic inflammatory diseases.