Academic Neurosurgery Unit, St. George's, University of London, London, UK.
Ann Neurol. 2012 Mar;71(3):323-33. doi: 10.1002/ana.22686. Epub 2012 Feb 28.
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system associated with pathogenic autoantibodies against the astrocyte water channel protein aquaporin-4 (AQP4). The presence of neutrophils is a characteristic feature in NMO lesions in humans. Neutrophils are not generally found in multiple sclerosis lesions. We evaluated the role of neutrophils in a mouse NMO model.
NMO lesions were produced in mice by intracerebral injection of immunoglobulin G (IgG) isolated from NMO patient serum and human complement. We previously reported that this mouse model produces the characteristic histological features of NMO, including perivascular complement activation, inflammatory cell infiltration, and loss of myelin, AQP4, and glial fibrillary acidic protein. Lesions are absent when AQP4 null mice are used or when IgG from non-NMO patients is injected.
We found remarkably reduced neuroinflammation, myelin loss, and AQP4 loss in brains of neutropenic mice at 24 hours and 7 days, and increased severity of NMO lesions in mice made neutrophilic by granulocyte colony stimulating factor. NMO lesions were greatly reduced by intracerebral administration of the neutrophil protease inhibitors Sivelestat and cathepsin G inhibitor I or by intraperitoneal injection of Sivelestat alone. Immunostaining of human NMO lesions for neutrophil elastase revealed many degranulating perivascular neutrophils, with no equivalent perivascular neutrophils in human multiple sclerosis lesions.
Our data implicate a central role of neutrophils in the pathogenesis of early NMO lesions and suggest the potential utility of neutrophil protease inhibitors such as Sivelestat in NMO therapy.
视神经脊髓炎（NMO）是一种中枢神经系统的炎症性脱髓鞘疾病，与针对星形胶质细胞水通道蛋白 aquaporin-4（AQP4）的致病性自身抗体有关。中性粒细胞的存在是人类 NMO 病变的一个特征。中性粒细胞通常不会出现在多发性硬化症病变中。我们评估了中性粒细胞在小鼠 NMO 模型中的作用。
通过向小鼠脑内注射从 NMO 患者血清中分离的免疫球蛋白 G（IgG）和人补体，产生 NMO 病变。我们之前报道过，这种小鼠模型产生 NMO 的特征组织学特征，包括血管周围补体激活、炎症细胞浸润和髓鞘、AQP4 和神经胶质纤维酸性蛋白丢失。当使用 AQP4 缺失小鼠或注射非 NMO 患者的 IgG 时，不会产生病变。
我们发现中性粒细胞缺失小鼠在 24 小时和 7 天时的神经炎症、髓鞘丢失和 AQP4 丢失明显减少，而通过粒细胞集落刺激因子使小鼠产生中性粒细胞时 NMO 病变的严重程度增加。通过脑内给予中性粒细胞蛋白酶抑制剂西维来司他和组织蛋白酶 G 抑制剂 I，或单独腹腔注射西维来司他，可大大减少 NMO 病变。对人类 NMO 病变进行中性粒细胞弹性蛋白酶免疫染色显示，许多血管周围有脱颗粒的中性粒细胞，而在人类多发性硬化症病变中则没有等效的血管周围中性粒细胞。
我们的数据表明中性粒细胞在早期 NMO 病变的发病机制中起核心作用，并提示中性粒细胞蛋白酶抑制剂如西维来司他在 NMO 治疗中的潜在应用价值。
