REELIN – A NOVEL TARGET FOR THE PREVENTION OF INFLAMMATORY DISEASE

• Applicant: Dr. Laurent Calvier
• Subject Area: Cardiology, Angiology ; Cell Biology
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 370877782

Atherosclerosis is a progressive chronic disease characterized by arterial accumulation of lipid and cholesterol in plaques. It is an inflammatory process, starting in the arteries with endothelial dysfunction increasing inflammatory marker secretion, followed by leukocyte and monocyte extravasation. Lipoproteins and receptors play a central role in inflammation during atherosclerosis development. Interestingly in arterial endothelial cells, the Apolipoprotein E receptor-2 (Apoer2), an LDL receptor (LDLR) family member, is involved in inflammatory marker secretion (vascular cell adhesion molecule-1, VCAM-1) and in leukocyte–endothelial cell adhesion. Reelin, originally described in the neurones, binds to Apoer2, leading to phosphorylation of the intracellular adapter protein Disabled-1 (Dab1) by Src-family tyrosine kinases and thereby controling various cellular functions. Circulating Reelin has been recently described to promote atherosclerosis by elevating the basal state of vascular immune surveillance. In the atherosclerosis-prone LDLR-deficient mouse model, Reelin deletion decreased atherosclerosis progression by reducing leukocyte-endothelial adhesion and expression of the pro-inflammatory markers VCAM-1 and intercellular adhesion molecule-1 (ICAM-1). Thus, reduction of Reelin in the plasma is sufficient to protect the vascular wall from cholesterol-induced atherosclerosis.Therefore, we hypothesized that reducing or inhibiting circulating Reelin, for instance with neutralizing antibodies presents a novel conceptual strategy for the prevention of cardiovascular disease. I will further explore these approaches with the goal of defining in detail the molecular mechanisms by which Reelin increases leukocyte adhesion to the vascular wall. The implication of Reelin in atherosclerosis is a completely new, groundbreaking, finding. It opens a broad field to identify the cellular mechanism involved in leukocyte or monocyte extravasation. Beyond the understanding of the signaling, the expected outcome of this project is to establish if plasmatic Reelin could be a relevant biomarker of atherosclerosis, helping clinicians to establish advanced personalized anti-atherosclerosis treatments. Then, reelin targeting with neutralizing antibodies could provide a novel therapeutical approach to counteract leukocyte or monocyte extravasation and prevent progression of the disease. Finally, this work is useful not only for atherosclerosis, but it is also relevant for diseases that involve leukocyte or monocyte extravasation as a central pathological mechanism, such as Multiple Sclerosis.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Joachim Herz