Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Changchun, China.
First Operating Room, The First Hospital of Jilin University, Changchun, China.
Ann Clin Transl Neurol. 2024 Oct;11(10):2731-2744. doi: 10.1002/acn3.52188. Epub 2024 Sep 2.
Neuromyelitis optica spectrum disorder (NMOSD) is an anti-aquaporin 4 (anti-AQP4) autoantibodies-mediated idiopathic inflammatory demyelinating disease of the central nervous system. While intravenous pulse methylprednisolone (IVMP) is the recommended initial treatment option for acute onset NMOSD, its therapeutic mechanism remains unclear. We hypothesized that IVMP would reduce the expression of pro-inflammatory factors and increase the resolution of inflammation in patients with NMOSD.
Mendelian randomization (MR) analysis was used to screen meaningful inflammatory and resolution factors for inclusion. Three MR methods with inverse variance weighting (IVW) were primarily used to identify positive results. Interleukin (IL)-10, IL-1β, IL-6, C-X-C motif chemokine ligand 12 (CXCL12), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were screened from 41 inflammatory factors, and resolvin D1 (RvD1), maresin 1 (MaR1), and lipoxin A4 (LXA4) were screened from 6 resolution markers for inclusion. Subsequently, 12 patients with NMOSD were enrolled and treated with IVMP. Serum levels of the aforementioned inflammatory and resolution markers were measured by enzyme-linked immunosorbent assay before and after IVMP treatment.
High levels of TRAIL, CXCL12, and IL-1β were associated with an increased risk of NMOSD (TRAIL: odds ratio [OR], 1.582; 95% confidence interval [CI], 1.003-2.495; CXCL12: OR, 3.610; 95% CI, 1.011-12.889; IL-1β: OR, 4.500; 95% CI, 1.129-17.927). High levels of RvD1, MaR1, and LXA4 were associated with a reduced risk of NMOSD (RvD1: OR, 0.725; 95% CI, 0.538-0.976; MaR1: OR, 0.985; 95% CI, 0.970-0.999; LXA4: OR, 0.849; 95% CI, 0.727-0.993). Among patients with NMOSD, serum levels of IL-6, CXCL12, and TRAIL significantly decreased following IVMP treatment, compared with pretreatment levels, while levels of IL-1β, LXA4, and MaR1 significantly increased after IVMP treatment (p < 0.05). A significant positive correlation was observed between CXCL12 levels and Expanded Disability Status Scale (EDSS) scores (r = 0.451, p < 0.05).
Several systemic inflammatory regulators associated with the pathogenesis of NMOSD were identified. The protective roles of LXA4 and MaR1 may be indispensable components of glucocorticoid treatment. Therefore, the use of resolution markers may be a potential strategy for improving central nervous system injury in individuals with NMOSD.
视神经脊髓炎谱系疾病（NMOSD）是一种抗水通道蛋白 4（抗-AQP4）自身抗体介导的中枢神经系统特发性炎症性脱髓鞘疾病。虽然静脉注射甲基泼尼松龙（IVMP）是急性发作 NMOSD 的推荐初始治疗选择，但它的治疗机制仍不清楚。我们假设 IVMP 将降低促炎因子的表达并增加 NMOSD 患者的炎症消退。
采用孟德尔随机化（MR）分析筛选有意义的炎症和消退因子。主要使用逆方差加权（IVW）的三种 MR 方法来确定阳性结果。从 41 种炎症因子中筛选白细胞介素（IL）-10、IL-1β、IL-6、C-X-C 基序趋化因子配体 12（CXCL12）和肿瘤坏死因子相关凋亡诱导配体（TRAIL），从 6 种消退标志物中筛选出消退素 D1（RvD1）、maresin 1（MaR1）和脂氧素 A4（LXA4）。随后，纳入 12 例 NMOSD 患者，给予 IVMP 治疗。通过酶联免疫吸附试验测定治疗前后患者血清中上述炎症和消退标志物的水平。
高水平的 TRAIL、CXCL12 和 IL-1β 与 NMOSD 的发病风险增加相关（TRAIL：比值比 [OR]，1.582；95%置信区间 [CI]，1.003-2.495；CXCL12：OR，3.610；95%CI，1.011-12.889；IL-1β：OR，4.500；95%CI，1.129-17.927）。高水平的 RvD1、MaR1 和 LXA4 与 NMOSD 的发病风险降低相关（RvD1：OR，0.725；95%CI，0.538-0.976；MaR1：OR，0.985；95%CI，0.970-0.999；LXA4：OR，0.849；95%CI，0.727-0.993）。与治疗前相比，NMOSD 患者经 IVMP 治疗后血清中 IL-6、CXCL12 和 TRAIL 水平显著降低，而 IL-1β、LXA4 和 MaR1 水平显著升高（p<0.05）。CXCL12 水平与扩展残疾状况量表（EDSS）评分呈显著正相关（r=0.451，p<0.05）。
鉴定出与 NMOSD 发病机制相关的几种系统性炎症调节因子。LXA4 和 MaR1 的保护作用可能是糖皮质激素治疗不可或缺的组成部分。因此，使用消退标志物可能是改善 NMOSD 患者中枢神经系统损伤的潜在策略。
