Lipocalin-2 is increased in progressive multiple sclerosis and inhibits remyelination.
Lipocalin-2 is increased in progressive multiple sclerosis and inhibits remyelination.
复制标题
DOI：
10.1212/nxi.0000000000000191
复制
发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Piehl F
中科院分区：
文献类型：
--
作者：
Al Nimer F;Elliott C;Bergman J;Khademi M;Dring AM;Aeinehband S;Bergenheim T;Romme Christensen J;Sellebjerg F;Svenningsson A;Linington C;Olsson T;Piehl F
我们的目的是研究脂质运载蛋白-2 (LCN2) 在多发性硬化症 (MS) 中的调节及其与髓鞘形成和神经变性的潜在功能相关性。我们在 3 项不同的研究中确定了 LCN2 水平：(1) 一项病例对照研究中的脑脊液和血浆中的 LCN2 水平，该研究将 MS 患者 (n = 147) 与对照组 (n = 50) 以及复发缓解型 MS 患者 (n = 75) 与进展型 MS 患者 (n = 72) 进行比较； (2) 来自 7 名进行性多发性硬化症患者的病例系列的脑脊液和脑组织微透析液； (3) 在一项对 17 名进展型多发性硬化症患者进行的队列研究中，基线时和那他珠单抗治疗后 60 周的脑脊液检测结果。测试了与神经丝光（神经轴突损伤标志物）的相关性。在大鼠体外神经胶质细胞共培养模型中研究了 LCN2 对髓鞘形成和神经变性的影响。 LCN2 的鞘内产生主要在进展型 MS 患者中增加（与复发缓解型 MS 相比，p < 0.005），并且与神经丝光呈正相关（p = 0.005）。脑微透析液中的 LCN2 水平比脑脊液中的高几倍，表明进行性多发性硬化症中局部产生 LCN2。用那他珠单抗治疗进展型 MS 可使 LCN2 水平平均降低 13% (p < 0.0001)。发现 LCN2 在体外以剂量依赖性方式抑制髓鞘再生。 LCN2 的产生主要在进行性 MS 中增加。尽管这种适度的增加不支持使用 LCN2 作为生物标志物，但与神经丝光的相关性和对髓鞘再生的抑制作用表明，LCN2 可能通过髓鞘形成依赖性途径导致神经退行性变。
We aimed to examine the regulation of lipocalin-2 (LCN2) in multiple sclerosis (MS) and its potential functional relevance with regard to myelination and neurodegeneration. We determined LCN2 levels in 3 different studies: (1) in CSF and plasma from a case-control study comparing patients with MS (n = 147) with controls (n = 50) and patients with relapsing-remitting MS (n = 75) with patients with progressive MS (n = 72); (2) in CSF and brain tissue microdialysates from a case series of 7 patients with progressive MS; and (3) in CSF at baseline and 60 weeks after natalizumab treatment in a cohort study of 17 patients with progressive MS. Correlation to neurofilament light, a marker of neuroaxonal injury, was tested. The effect of LCN2 on myelination and neurodegeneration was studied in a rat in vitro neuroglial cell coculture model. Intrathecal production of LCN2 was increased predominantly in patients with progressive MS (p < 0.005 vs relapsing-remitting MS) and displayed a positive correlation to neurofilament light (p = 0.005). Levels of LCN2 in brain microdialysates were severalfold higher than in the CSF, suggesting local production in progressive MS. Treatment with natalizumab in progressive MS reduced LCN2 levels an average of 13% (p < 0.0001). LCN2 was found to inhibit remyelination in a dose-dependent manner in vitro. LCN2 production is predominantly increased in progressive MS. Although this moderate increase does not support the use of LCN2 as a biomarker, the correlation to neurofilament light and the inhibitory effect on remyelination suggest that LCN2 might contribute to neurodegeneration through myelination-dependent pathways.