Departments of Medicine and Physiology, University of California, 1246 Health Sciences East Tower, 513 Parnassus Ave, San Francisco, CA, 94143-0521, USA.
Department of Neurology, Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China.
J Neuroinflammation. 2019 Mar 9;16(1):57. doi: 10.1186/s12974-019-1448-x.
Neuromyelitis optica spectrum disorder (herein called NMO) is an inflammatory demyelinating disease that can be initiated by binding of immunoglobulin G autoantibodies (AQP4-IgG) to aquaporin-4 on astrocytes, causing complement-dependent cytotoxicity (CDC) and downstream inflammation. The increased NMO pathology in rodents deficient in complement regulator protein CD59 following passive transfer of AQP4-IgG has suggested the potential therapeutic utility of increasing the expression of complement regulator proteins.
A cell-based ELISA was developed to screen for pharmacological upregulators of endogenous CD55 and CD59 in a human astrocyte cell line. A statin identified from the screen was characterized in cell culture models and rodents for its action on complement regulator protein expression and its efficacy in models of seropositive NMO.
Screening of ~ 11,500 approved and investigational drugs and nutraceuticals identified transcriptional upregulators of CD55 but not of CD59. Several statins, including atorvastatin, simvastatin, lovastatin, and fluvastatin, increased CD55 protein expression in astrocytes, including primary cultures, by three- to four-fold at 24 h, conferring significant protection against AQP4-IgG-induced CDC. Mechanistic studies revealed that CD55 upregulation involves inhibition of the geranylgeranyl transferase pathway rather than inhibition of cholesterol biosynthesis. Oral atorvastatin at 10-20 mg/kg/day for 3 days strongly increased CD55 immunofluorescence in mouse brain and spinal cord and reduced NMO pathology following intracerebral AQP4-IgG injection.
Atorvastatin or other statins may thus have therapeutic benefit in AQP4-IgG seropositive NMO by increasing CD55 expression, in addition to their previously described anti-inflammatory and immunomodulatory actions.
视神经脊髓炎谱系疾病（以下简称 NMO）是一种炎症性脱髓鞘疾病，可由免疫球蛋白 G 自身抗体（AQP4-IgG）与星形胶质细胞上的水通道蛋白 4 结合引发，导致补体依赖性细胞毒性（CDC）和下游炎症。AQP4-IgG 被动转移后，补体调节蛋白 CD59 缺陷的啮齿动物中 NMO 病理学增加，这表明增加补体调节蛋白表达具有潜在的治疗效用。
开发了一种基于细胞的 ELISA 法，用于筛选人星形胶质细胞系中内源性 CD55 和 CD59 的药理学上调物。从筛选中鉴定出的一种他汀类药物在细胞培养模型和啮齿动物中进行了表征，以研究其对补体调节蛋白表达的作用及其在血清阳性 NMO 模型中的疗效。
对约 11500 种已批准和正在研究的药物和营养保健品进行筛选，发现了 CD55 的转录上调物，但未发现 CD59 的转录上调物。几种他汀类药物，包括阿托伐他汀、辛伐他汀、洛伐他汀和氟伐他汀，可在 24 小时内将星形胶质细胞（包括原代培养物）中的 CD55 蛋白表达增加三到四倍，从而显著对抗 AQP4-IgG 诱导的 CDC。机制研究表明，CD55 上调涉及抑制法尼基转移酶途径，而不是抑制胆固醇生物合成。阿托伐他汀或其他他汀类药物在 3 天内每天口服 10-20mg/kg，可强烈增加小鼠大脑和脊髓中的 CD55 免疫荧光，并减少脑内 AQP4-IgG 注射后的 NMO 病理学。
阿托伐他汀或其他他汀类药物可能通过增加 CD55 表达，除了其先前描述的抗炎和免疫调节作用外，在 AQP4-IgG 血清阳性 NMO 中具有治疗益处。
