Department of Molecular Cell Biology and Immunology, VU University Medical Center Amsterdam, Neuroscience Campus, Amsterdam, The Netherlands.
Department of Pathology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
Eur J Immunol. 2015 Jun;45(6):1808-19. doi: 10.1002/eji.201444960. Epub 2015 May 3.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Infiltration of monocytes into the CNS is crucial for disease onset and progression. Animal studies indicate that granulocyte-macrophages colony-stimulating factor (GM-CSF) may play an essential role in this process, possibly by acting on the migratory capacities of myeloid cells across the blood-brain barrier. This study describes the effect of GM-CSF on human monocytes, macrophages, and microglia. Furthermore, the expression of GM-CSF and its receptor was investigated in the CNS under healthy and pathological conditions. We show that GM-CSF enhances monocyte migration across human blood-brain barrier endothelial cells in vitro. Next, immunohistochemical analysis on human brain tissues revealed that GM-CSF is highly expressed by microglia and macrophages in MS lesions. The GM-CSF receptor is expressed by neurons in the rim of combined gray/white matter lesions and astrocytes. Finally, the effect of GM-CSF on human macrophages was determined, revealing an intermediate activation status, with a phenotype similar to that observed in active MS lesions. Together our data indicate that GM-CSF is a powerful stimulator of monocyte migration, and is abundantly present in the inflamed CNS where it may act as an activator of macrophages and microglia.
多发性硬化症 (MS) 是一种中枢神经系统 (CNS) 的慢性炎症性脱髓鞘疾病。单核细胞浸润中枢神经系统对于疾病的发生和进展至关重要。动物研究表明，粒细胞-巨噬细胞集落刺激因子 (GM-CSF) 可能在此过程中发挥重要作用，可能通过作用于血脑屏障穿透能力的髓样细胞。本研究描述了 GM-CSF 对人单核细胞、巨噬细胞和小胶质细胞的影响。此外，还研究了 GM-CSF 及其受体在健康和病理条件下中枢神经系统中的表达。我们发现 GM-CSF 可增强单核细胞在体外穿过人血脑屏障内皮细胞的迁移能力。接下来，对人脑组织的免疫组织化学分析显示，GM-CSF 在 MS 病变中的小胶质细胞和巨噬细胞中高度表达。GM-CSF 受体在灰质/白质混合病变边缘的神经元和星形胶质细胞中表达。最后，确定了 GM-CSF 对人巨噬细胞的影响，发现其具有中间激活状态，表型类似于活跃 MS 病变中观察到的表型。综上所述，我们的数据表明 GM-CSF 是单核细胞迁移的强大刺激物，并且在炎症中枢神经系统中大量存在，可能作为巨噬细胞和小胶质细胞的激活剂。
