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

Bosch Queralt, Mar (2020): Diet-dependent regulation of TGFβ impairs reparative innate immune responses after demyelination: investigating a therapeutic approach to enhance remyelination. Dissertation, LMU München: Fakultät für Biologie

Abstract

Multiple sclerosis (MS) is one of the most common causes of chronic disability in young adults. In 85% of the cases, the disease starts with a relapsing-remitting course but, as age advances, the majority of patients enter a progressive phase of the disease characterized by neurological decline and brain atrophy. Treatments that delay, prevent or reverse this progression phase are an unmet need in MS research. The cause of progressive MS is not known, but remyelination failure may contribute. Hence, large efforts have been directed into identifying strategies to enhance endogenous remyelination, which can prevent neuronal death. Microglia are the immune cells of the central nervous system (CNS) and play a crucial role in orchestrating remyelination. With ageing, microglia do not respond adequately to myelin damage, leading to failed remyelination. Apart from ageing, clinical observations suggest that also obesity increases the risk of progression in MS. However, whether and how obesity might influence remyelination is not known. In this study, we use western diet (WD) to induce obesity in mice and investigate the impact of WD on microglia’s response to demyelination. With this, we aim to understand how obesity might affect the pro-regenerative functions of microglia. Since the metabolism of myelin-derived lipids by microglia is an essential step for successful remyelination, we further examine how WD changes the lipid composition of the plasma and brain and whether these changes have consequences on microglia’s response to demyelination. We find that WD consumption leads to impaired remyelination after toxin-induced demyelination due to deficient cholesterol efflux by microglia. Furthermore, we show that WD intake alters the lipid profile of the brain white and grey matter, is associated with modest microgliosis in the corpus callosum, and causes an increase in transforming growth factor-β (TGFβ) in the brain. Such excess TGFβ signalling leads to insufficient microglia response to damage and impaired cholesterol efflux, which ultimately prevents inflammation resolution and remyelination. By blocking TGFβ signalling or enhancing microglia activation through triggering-receptor expressed on myeloid cells 2 (TREM2), we could promote adequate microglia activation and successful resolution of damage in the CNS. Hence, we unravel a microglia immune checkpoint mechanism as a potential therapeutic target to promote a reparative inflammatory response after demyelinating injury. In conclusion, our study demonstrates that obesity leads to failed remyelination by disturbing the pro-regenerative functions of microglia. In addition, our findings expand the spectrum of potential therapeutic strategies to enhance endogenous remyelination.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Fakultät für Biologie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 8. September 2020
• 1. Bericht­erstatter:in: Simons, Mikael