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
特雷姆2
神经科学
生物
病理
多发性硬化
炎症
疾病
遗传学
作者
Chuan Qin,Man Chen,Minghao Dong,Sheng Qiang 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
标识
DOI:10.1093/brain/awad321
摘要
Abstract 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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