Department of Molecular Cell Biology and Immunology, MS Center Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands.
Acta Neuropathol. 2012 Sep;124(3):397-410. doi: 10.1007/s00401-012-1014-4. Epub 2012 Jul 19.
Alterations in sphingolipid metabolism are described to contribute to various neurological disorders. We here determined the expression of enzymes involved in the sphingomyelin cycle and their products in postmortem brain tissue of multiple sclerosis (MS) patients. In parallel, we investigated the effect of the sphingosine-1 receptor agonist Fingolimod (Gilenya(®)) on sphingomyelin metabolism in reactive astrocytes and determined its functional consequences for the process of neuro-inflammation. Our results demonstrate that in active MS lesions, marked by large number of infiltrated immune cells, an altered expression of enzymes involved in the sphingomyelin cycle favors enhanced ceramide production. We identified reactive astrocytes as the primary cellular source of enhanced ceramide production in MS brain samples. Astrocytes isolated from MS lesions expressed enhanced mRNA levels of the ceramide-producing enzyme acid sphingomyelinase (ASM) compared to astrocytes isolated from control white matter. In addition, TNF-α treatment induced ASM mRNA and ceramide levels in astrocytes isolated from control white matter. Incubation of astrocytes with Fingolimod prior to TNF-α treatment reduced ceramide production and mRNA expression of ASM to control levels in astrocytes. Importantly, supernatants derived from reactive astrocytes treated with Fingolimod significantly reduced transendothelial monocyte migration. Overall, the present study demonstrates that reactive astrocytes represent a possible additional cellular target for Fingolimod in MS by directly reducing the production of pro-inflammatory lipids and limiting subsequent transendothelial leukocyte migration.
鞘脂代谢的改变被描述为导致各种神经紊乱的原因。在这里，我们确定了鞘脂循环中涉及的酶及其产物在多发性硬化症（MS）患者死后脑组织中的表达。同时，我们研究了鞘氨醇-1 受体激动剂 fingolimod（Gilenya(®)）对反应性星形胶质细胞中鞘脂代谢的影响，并确定了其对神经炎症过程的功能后果。我们的结果表明，在活跃的 MS 病变中，大量浸润的免疫细胞标记，鞘脂循环中涉及的酶的表达改变有利于增强神经酰胺的产生。我们将反应性星形胶质细胞鉴定为 MS 脑样本中增强神经酰胺产生的主要细胞来源。与从对照白质分离的星形胶质细胞相比，从 MS 病变中分离的星形胶质细胞表达增强的产生神经酰胺的酶酸性鞘磷脂酶（ASM）的 mRNA 水平。此外，TNF-α 处理诱导了从对照白质中分离的星形胶质细胞中的 ASM mRNA 和神经酰胺水平。在 TNF-α 处理之前用 fingolimod 孵育星形胶质细胞可将神经酰胺的产生和 ASM 的 mRNA 表达降低至星形胶质细胞中的对照水平。重要的是，用 fingolimod 处理的反应性星形胶质细胞的上清液显著降低了跨内皮单核细胞迁移。总的来说，本研究表明，反应性星形胶质细胞通过直接减少促炎脂质的产生和限制随后的跨内皮白细胞迁移，代表了 MS 中 fingolimod 的另一个可能的细胞靶标。
