TY - JOUR
T1 - Diet-dependent regulation of TGFβ impairs reparative innate immune responses after demyelination
AU - Bosch-Queralt, Mar
AU - Cantuti-Castelvetri, Ludovico
AU - Damkou, Alkmini
AU - Schifferer, Martina
AU - Schlepckow, Kai
AU - Alexopoulos, Ioannis
AU - Lütjohann, Dieter
AU - Klose, Christian
AU - Vaculčiaková, Lenka
AU - Masuda, Takahiro
AU - Prinz, Marco
AU - Monroe, Kathryn M.
AU - Di Paolo, Gilbert
AU - Lewcock, Joseph W.
AU - Haass, Christian
AU - Simons, Mikael
N1 - Funding Information:
The work was supported by grants from the German Research Foundation (SPP2191, TRR1282, TRR 274 Project ID 408885537, Koselleck Project HA1737/161, SyNergy Excellence Cluster, EXC2145, Projekt ID390857198), the Human Frontier Science Program (HFSP), the ERC (Consolidator Grant to M.S.), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. M.B.Q. was supported by a Boehringer Ingelheim Fonds PhD fellowship. We would like to thank A. Rhomberg, G. Kislinger, A. Kerksiek and K. Karg for their technical assistance.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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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U2 - 10.1038/s42255-021-00341-7
DO - 10.1038/s42255-021-00341-7
M3 - Article
C2 - 33619376
AN - SCOPUS:85101335586
SN - 2522-5812
VL - 3
SP - 211
EP - 227
JO - Nature Metabolism
JF - Nature Metabolism
IS - 2
ER -
