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.

免疫细胞招募至中枢神经系统 (CNS) 导致的神经炎症是多发性硬化症 (MS) 的关键致病机制。然而，目前的抗炎干预措施消耗免疫细胞或直接将其运输到中枢神经系统，可能会产生严重的副作用，这凸显了对更好的免疫调节策略的需要。我们检测到 MS 患者血清中 Reelin 浓度增加，通过增加核因子 κB 介导的血管粘附分子表达，导致内皮细胞对白细胞的通透性增加。因此，我们研究了 Reelin 免疫耗竭对实验性自身免疫性脑脊髓炎 (EAE) 的预防和治疗潜力，并进一步在 Reelin 敲除小鼠中验证了结果。通过这两种方法去除血浆 Reelin 可以防止神经炎症，并通过降低中枢神经系统内皮通透性和免疫细胞积累来很大程度上消除神经系统后果。我们的研究结果表明，Reelin 去除作为一种治疗方法，对于治疗多发性硬化症和白细胞外渗是致病性主要驱动因素的其他疾病具有固有的良好安全性。