期刊
JCI INSIGHT
卷 2, 期 8, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.87455
关键词
-
资金
- European Commission [264083]
- Hellenic General Secretariat of Research and Technology through the National Action Cooperation project [09SYN-21-609]
- Operational Program project [KRIPIS MIS450598]
- Hellenic Academy of Neuroimmunology (HELANI) from Teva Pharmaceutical Industries LTD
- Cluster of Excellence
- DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain, Gottingen, Germany
Multiple sclerosis (MS) is an inflammatory CNS demyelinating disease in which remyelination largely fails. Transmembrane TNF (tmTNF) and TNF receptor 2 are important for remyelination in experimental MS models, but it is unknown whether soluble TNF (solTNF), a major proinflammatory factor, is involved in regeneration processes. Here, we investigated the specific contribution of solTNF to demyelination and remyelination in the cuprizone model. Treatment with XPro1595, a selective inhibitor of solTNF that crosses the intact blood-brain barrier (BBB), in cuprizone-fed mice did not prevent toxin-induced oligodendrocyte loss and demyelination, but it permitted profound early remyelination due to improved phagocytosis of myelin debris by CNS macrophages and prevented disease-associated decline in motor performance. The beneficial effects of XPro1595 were absent in TNF-deficient mice and replicated in tmTNF-knockin mice, showing that tmTNF is sufficient for the maintenance of myelin and neuroprotection. These findings demonstrate that solTNF inhibits remyelination and repair in a cuprizone demyelination model and suggest that local production of solTNF in the CNS might be one reason why remyelination fails in MS. These findings also suggest that disinhibition of remyelination by selective inhibitors of solTNF that cross the BBB might represent a promising approach for treatment in progressive MS.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据