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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. PMID: 33619376.

Authors/Editors: Bosch-Queralt M, Cantuti-Castelvetri L, Damkou A, Schifferer M, Schlepckow K, Alexopoulos I, Lütjohann D, Klose C, Vaculčiaková L, Masuda T, Prinz M, Monroe KM, Di Paolo G, Lewcock JW, Haass C, Simons M.
Publication Date: 2021

Abstract

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.

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