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

Nat Metab. 2021 Feb;3(2):211-227. doi: 10.1038/s42255-021-00341-7. Epub 2021 Feb 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism
  • Animals
  • Cholesterol / metabolism
  • Demyelinating Diseases / immunology*
  • Demyelinating Diseases / metabolism*
  • Diet*
  • Diet, Western
  • Immunity, Innate / immunology*
  • Liver X Receptors
  • Lysophosphatidylcholines / pharmacology
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microglia / metabolism
  • Myelin Sheath / metabolism
  • Phagocytes / metabolism
  • Receptors, Immunologic / metabolism
  • Transforming Growth Factor beta / metabolism*


  • Liver X Receptors
  • Lysophosphatidylcholines
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Transforming Growth Factor beta
  • Trem2 protein, mouse
  • Cholesterol