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

Bosch-Queralt, M., Cantuti-Castelvetri, L., Damkou, A., Schifferer, M., Schlepckow, K., Alexopoulos, I., et al. (2021). Diet-dependent regulation of TGFβ impairs reparative innate immune responses after demyelination. Nature Metabolism, 3, 211-227. doi:10.1038/s42255-021-00341-7.

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Bosch-Queralt, Mar1, 2, Author
Cantuti-Castelvetri, Ludovico1, 2, Author
Damkou, Alkmini1, 2, Author
Schifferer, Martina2, 3, Author
Schlepckow, Kai2, Author
Alexopoulos, Ioannis1, 2, Author
Lütjohann, Dieter4, Author
Klose, Christian5, Author
Vaculciakova, Lenka6, Author              
Masuda, Takahiro7, Author
Prinz, Marco7, 8, 9, Author
Monroe, Kathryn M.10, Author
Di Paolo, Gilbert10, Author
Lewcock, Joseph W.10, Author
Haass, Christian2, 3, 11, Author
Simons, Mikael1, 2, 3, Author
Affiliations:
1Institute of Neuronal Cell Biology, TU Munich, Germany, ou_persistent22              
2German Center for Neurodegenerative Diseases, Munich, Germany, ou_persistent22              
3Munich Cluster for Systems Neurology (SyNergy), Germany, ou_persistent22              
4Institute for of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Germany, ou_persistent22              
5Lipotype, Dresden, Germany, ou_persistent22              
6Department Neurophysics (Weiskopf), MPI for Human Cognitive and Brain Sciences, Max Planck Society, ou_2205649              
7Institute of Neuropathology, University Medical Center, Freiburg, Germany, ou_persistent22              
8BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University Freiburg, Germany, ou_persistent22              
9Center for Basics in NeuroModulation (NeuroModulBasics), Albert Ludwigs University Freiburg, Germany, ou_persistent22              
10Denali Therapeutics Inc., South San Francisco, CA, USA, ou_persistent22              
11Chair of Metabolic Biochemistry, Biomedical Center (BMC), Ludwig Maximilians University Munich, Germany, ou_persistent22              

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 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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Language(s): eng - English
 Dates: 2020-02-192021-01-082021-02-18
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/s42255-021-00341-7
Other: epub 2021
PMID: 33619376
PMC: PMC7610359
 Degree: -

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Title: Nature Metabolism
Source Genre: Journal
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Publ. Info: London : Springer Nature
Pages: - Volume / Issue: 3 Sequence Number: - Start / End Page: 211 - 227 Identifier: ISSN: 2522-5812
CoNE: https://pure.mpg.de/cone/journals/resource/2522-5812