再髓鞘化
小胶质细胞
髓鞘
先天免疫系统
免疫学
免疫系统
脱髓鞘病
生物
炎症
细胞生物学
癌症研究
神经科学
多发性硬化
中枢神经系统
作者
Mar Bosch-Queralt,Ludovico Cantuti-Castelvetri,Alkmini Damkou,Martina Schifferer,Kai Schlepckow,Ioannis Alexopoulos,Dieter Lütjohann,Christian Klose,Lenka Vaculčiaková,Takahiro Masuda,Marco Prinz,Kathryn M. Monroe,Gilbert Di Paolo,Joseph W. Lewcock,Christian Haass,Mikael Simons
标识
DOI:10.1038/s42255-021-00341-7
摘要
Proregenerative responses are required for the restoration of nervous-system functionality in demyelinating diseases such as multiple sclerosis (MS). Yet, the limiting factors responsible for poor CNS repair are only partially understood. Here, we test the impact of a Western diet (WD) on phagocyte function in a mouse model of demyelinating injury that requires microglial innate immune function for a regenerative response to occur. We find that WD feeding triggers an ageing-related, dysfunctional metabolic response that is associated with impaired myelin-debris clearance in microglia, thereby impairing lesion recovery after demyelination. Mechanistically, we detect enhanced transforming growth factor beta (TGFβ) signalling, which suppresses the activation of the liver X receptor (LXR)-regulated genes involved in cholesterol efflux, thereby inhibiting phagocytic clearance of myelin and cholesterol. Blocking TGFβ or promoting triggering receptor expressed on myeloid cells 2 (TREM2) activity restores microglia responsiveness and myelin-debris clearance after demyelinating injury. Thus, we have identified a druggable microglial immune checkpoint mechanism regulating the microglial response to injury that promotes remyelination. Bosch-Queralt et al. find that diet-induced obesity impairs restoration of CNS demyelination through increased TGFβ-mediated suppression of cholesterol efflux.
科研通智能强力驱动
Strongly Powered by AbleSci AI