Research ArticleMultiple Sclerosis

Reelin depletion protects against autoimmune encephalomyelitis by decreasing vascular adhesion of leukocytes

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Science Translational Medicine  12 Aug 2020:
Vol. 12, Issue 556, eaay7675
DOI: 10.1126/scitranslmed.aay7675

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Relying on Reelin

In multiple sclerosis (MS), the recruitment of immune cell into the brain contributes to neuroinflammation and consequent demyelination. Current approaches for inhibiting cellular infiltration have been shown to have therapeutic effects but present complications. In this study, Calvier et al. showed that the protein Reelin could be a therapeutic target in MS. Reelin was increased during relapses in serum of patients with relapsing-remitting MS. Genetic Reelin depletion in a mouse model of MS prevented monocyte extravasation and prevented paralysis. Using a pharmacologic approach, the authors showed that prophylactic or therapeutic Reelin inhibition had therapeutic effect in mice, suggesting that Reelin inhibition might be effective for treating MS.

Abstract

Neuroinflammation as a result of immune cell recruitment into the central nervous system (CNS) is a key pathogenic mechanism of multiple sclerosis (MS). However, current anti-inflammatory interventions depleting immune cells or directly targeting their trafficking into the CNS can have serious side effects, highlighting a need for better immunomodulatory strategies. We detected increased Reelin concentrations in the serum of patients with MS, resulting in increased endothelial permeability to leukocytes through increased nuclear factor κB–mediated expression of vascular adhesion molecules. We thus investigated the prophylactic and therapeutic potential of Reelin immunodepletion in experimental autoimmune encephalomyelitis (EAE) and further validated the results in Reelin knockout mice. Removal of plasma Reelin by either approach protected against neuroinflammation and largely abolished the neurological consequences by reducing endothelial permeability and immune cell accumulation in the CNS. Our findings suggest Reelin depletion as a therapeutic approach with an inherent good safety margin for the treatment of MS and other diseases where leukocyte extravasation is a major driver of pathogenicity.

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