Mailleux Jo, Timmermans Silke, Nelissen Katherine, Vanmol Jasmine, Vanmierlo Tim, van Horssen Jack, Bogie Jeroen F J, Hendriks Jerome J A
Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands.
Front Immunol. 2017 Nov 30;8:1701. doi: 10.3389/fimmu.2017.01701. eCollection 2017.
We aimed to determine the role of the low-density lipoprotein receptor (LDLr) in neuroinflammation by inducing experimental autoimmune encephalomyelitis (EAE) in knock out mice.
MOG induced EAE in male and female mice was assessed clinically and histopathologically. Expression of inflammatory mediators and apolipoprotein E (apoE) was investigated by qPCR. Changes in protein levels of apoE and tumor necrosis factor alpha (TNFα) were validated by western blot and ELISA, respectively.
-attenuated EAE disease severity in female, but not in male, EAE mice marked by a reduced proinflammatory cytokine production in the central nervous system of female mice. Macrophages from female mice showed a similar decrease in proinflammatory mediators, an impaired capacity to phagocytose myelin and enhanced secretion of the anti-inflammatory apoE. Interestingly, double knock out abrogated the beneficial effect of depletion in EAE.
Collectively, we show that reduces EAE disease severity in female but not in male EAE mice, and that this can be explained by increased levels of apoE in female mice. Although the reason for the observed sexual dimorphism remains unclear, our findings show that LDLr and associated apoE levels are involved in neuroinflammatory processes.
我们旨在通过在基因敲除小鼠中诱导实验性自身免疫性脑脊髓炎（EAE）来确定低密度脂蛋白受体（LDLr）在神经炎症中的作用。
对雄性和雌性小鼠中髓鞘少突胶质细胞糖蛋白（MOG）诱导的EAE进行临床和组织病理学评估。通过定量聚合酶链反应（qPCR）研究炎症介质和载脂蛋白E（apoE）的表达。分别通过蛋白质印迹法和酶联免疫吸附测定（ELISA）验证apoE和肿瘤坏死因子α（TNFα）蛋白水平的变化。
在雌性EAE小鼠中减轻了EAE疾病的严重程度，但在雄性EAE小鼠中未减轻，其特征是雌性小鼠中枢神经系统中促炎细胞因子产生减少。来自雌性小鼠的巨噬细胞显示促炎介质有类似的减少，吞噬髓鞘的能力受损以及抗炎性apoE的分泌增加。有趣的是，双基因敲除消除了LDLr缺失在EAE中的有益作用。
总体而言，我们表明LDLr缺失降低了雌性EAE小鼠而非雄性EAE小鼠的疾病严重程度，这可以通过雌性LDLr基因敲除小鼠中apoE水平的升高来解释。尽管观察到的性别差异的原因尚不清楚，但我们的研究结果表明LDLr和相关的apoE水平参与了神经炎症过程。
