神经炎症
小胶质细胞
视神经脊髓炎
免疫学
生物标志物
医学
神经退行性变
神经科学
生物
病理
多发性硬化
炎症
疾病
遗传学
作者
Chuanbo Qin,Man Chen,Minghao Dong,Sheng Yang,Hang Zhang,Yun‐Fan You,Luo‐Qi Zhou,Yun‐Hui Chu,Yue Tang,Xiao‐Wei Pang,Long‐Jun Wu,Dai‐Shi Tian,Wei Wang
出处
期刊:Brain
[Oxford University Press]
日期:2023-09-22
卷期号:147 (1): 163-176
被引量:5
标识
DOI:10.1093/brain/awad321
摘要
Microglia-mediated neuroinflammation contributes to acute demyelination in neuromyelitis optica spectrum disorders (NMOSD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF has been associated with microglial activation in several neurodegenerative diseases. However, the basis for this immune-mediated attack and the pathophysiological role of sTREM2 in NMOSD remain to be elucidated. Here, we performed Mendelian randomization analysis and identified a genetic association between increased CSF sTREM2 and NMOSD risk. CSF sTREM2 was elevated in patients with NMOSD and was positively correlated with neural injury and other neuroinflammation markers. Single-cell RNA sequencing of human macrophage/microglia-like cells in CSF, a proxy for microglia, showed that increased CSF sTREM2 was positively associated with microglial dysfunction in patients with NMOSD. Furthermore, we demonstrated that sTREM2 is a reliable biomarker of microglial activation in a mouse model of NMOSD. Using unbiased transcriptomic and lipidomic screens, we identified that excessive activation, overwhelmed phagocytosis of myelin debris, suppressed lipid metabolism and enhanced glycolysis underlie sTREM2-mediated microglial dysfunction, possibly through the nuclear factor kappa B (NF-κB) signalling pathway. These molecular and cellular findings provide a mechanistic explanation for the genetic association between CSF sTREM2 and NMOSD risk and indicate that sTREM2 could be a potential biomarker of NMOSD progression and a therapeutic target for microglia-mediated neuroinflammation.
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