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

Bosch-Queralt, Mar; Cantuti-Castelvetri, Ludovico; Damkou, Alkmini; Schifferer, Martina; Schlepckow, Kai; Alexopoulos, Ioannis; Luetjohann, Dieter; Klose, Christian; Vaculciakova, Lenka; Masuda, Takahiro; Prinz, Marco; Monroe, Kathryn M.; Di Paolo, Gilbert; Lewcock, Joseph W.; Haass, Christian und Simons, Mikael (2021): Diet-dependent regulation of TGF beta impairs reparative innate immune responses after demyelination. In: Nature Metabolism, Bd. 3, Nr. 2: S. 211-227

Abstract

Bosch-Queralt et al. find that diet-induced obesity impairs restoration of CNS demyelination through increased TGF beta-mediated suppression of cholesterol efflux. 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 (TGF beta) 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 TGF beta 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198