Diet-dependent regulation of TGFβ impairs reparative innate immune responses after demyelination

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

研究成果: Contribution to journalArticle査読

8 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)211-227
ページ数17
ジャーナルNature Metabolism
3
2
DOI
出版ステータス出版済み - 2 2021
外部発表はい

All Science Journal Classification (ASJC) codes

  • 内科学
  • 内分泌学、糖尿病および代謝内科学
  • 細胞生物学
  • 生理学(医学)

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