Valente Tony, Serratosa Joan, Perpiñá Unai, Saura Josep, Solà Carme
Department of Cerebral Ischemia and Neurodegeneration, Institut D'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas (CSIC), Institut D'Investigacions Biomèdiques August-Pi i Sunyer (IDIBAPS)Barcelona, Spain.
Biochemistry and Molecular Biology Unit, School of Medicine, Institut D'Investigacions Biomèdiques August-Pi i Sunyer (IDIBAPS), University of BarcelonaBarcelona, Spain.
Front Cell Neurosci. 2017 May 4;11:129. doi: 10.3389/fncel.2017.00129. eCollection 2017.
In the brain of patients with multiple sclerosis, activated microglia/macrophages appear in active lesions and in normal appearing white matter. However, whether they play a beneficial or a detrimental role in the development of the pathology remains a controversial issue. The production of pro-inflammatory molecules by chronically activated microglial cells is suggested to contribute to the progression of neurodegenerative processes in neurological disease. In the healthy brain, neurons control glial activation through several inhibitory mechanisms, such as the CD200-CD200R1 interaction. Therefore, we studied whether alterations in the CD200-CD200R1 system might underlie the neuroinflammation in an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. We determined the time course of CD200 and CD200R1 expression in the brain and spinal cord of an EAE mouse model from presymptomatic to late symptomatic stages. We also assessed the correlation with associated glial activation, inflammatory response and EAE severity. Alterations in CD200 and CD200R1 expression were mainly observed in spinal cord regions in the EAE model, mostly a decrease in CD200 and an increase in CD200R1 expression. A decrease in the expression of the mRNA encoding a full CD200 protein was detected before the onset of clinical signs, and remained thereafter. A decrease in CD200 protein expression was observed from the onset of clinical signs. By contrast, CD200R1 expression increased at EAE onset, when a glial reaction associated with the production of pro- and anti-inflammatory markers occurred, and continued to be elevated during the pathology. Moreover, the magnitude of the alterations correlated with severity of the EAE mainly in spinal cord. These results suggest that neuronal-microglial communication through CD200-CD200R1 interaction is compromised in EAE. The early decreases in CD200 expression in EAE suggest that this downregulation might also occur in the initial phases of multiple sclerosis, and that this early neuronal dysfunction might facilitate the development of neuroinflammation. The increased CD200R1 expression in the EAE model highlights the potential use of targeted agonist molecules as therapeutic tools to control neuroinflammation. In summary, the CD200-CD200R1 system is a potential therapeutic target in multiple sclerosis, and CD200R1 agonists are molecules that may be worth developing in this context.
在多发性硬化症患者的大脑中，活化的小胶质细胞/巨噬细胞出现在活跃病灶以及外观正常的白质中。然而，它们在病理发展过程中发挥有益还是有害作用仍是一个有争议的问题。慢性活化的小胶质细胞产生促炎分子，这被认为会促进神经退行性疾病中神经退行性过程的进展。在健康大脑中，神经元通过多种抑制机制控制胶质细胞的活化，比如CD200-CD200R1相互作用。因此，我们研究了CD200-CD200R1系统的改变是否可能是多发性硬化症实验性自身免疫性脑脊髓炎（EAE）模型中神经炎症的基础。我们确定了EAE小鼠模型从症状前期到症状后期大脑和脊髓中CD200和CD200R1表达的时间进程。我们还评估了其与相关胶质细胞活化、炎症反应和EAE严重程度的相关性。在EAE模型中，CD200和CD200R1表达的改变主要在脊髓区域观察到，大多是CD200表达降低，CD200R1表达增加。在临床症状出现之前就检测到编码完整CD200蛋白的mRNA表达下降，且此后一直保持下降。从临床症状出现开始观察到CD200蛋白表达下降。相比之下，CD200R1表达在EAE发病时增加，此时出现了与促炎和抗炎标志物产生相关的胶质反应，并且在病程中持续升高。此外，这些改变的程度主要在脊髓中与EAE的严重程度相关。这些结果表明，在EAE中，通过CD200-CD200R1相互作用的神经元-小胶质细胞通讯受到损害。EAE中CD200表达的早期下降表明这种下调也可能发生在多发性硬化症的初始阶段，并且这种早期神经元功能障碍可能会促进神经炎症的发展。EAE模型中CD200R1表达的增加突出了靶向激动剂分子作为控制神经炎症治疗工具的潜在用途。总之，CD200-CD200R1系统是多发性硬化症的一个潜在治疗靶点，CD200R1激动剂是在这种情况下可能值得开发的分子。
