Age-associated decline in regeneration capacity limits the restoration of nervous system functionality after injury. In a model for demyelination, we found that old mice fail to resolve the inflammatory response initiated after myelin damage. Aged phagocytes accumulated excessive amounts of myelin debris, which triggered cholesterol crystal formation and phagolysosomal membrane rupture and stimulated inflammasomes. Myelin debris clearance required cholesterol transporters, including apolipoprotein E. Stimulation of reverse cholesterol transport was sufficient to restore the capacity of old mice to remyelinate lesioned tissue. Thus, cholesterol-rich myelin debris can overwhelm the efflux capacity of phagocytes, resulting in a phase transition of cholesterol into crystals and thereby inducing a maladaptive immune response that impedes tissue regeneration.

Upon demyelinating injury, microglia orchestrate a regenerative response that promotes myelin repair, thereby restoring rapid signal propagation and protecting axons from further damage. Whereas the essential phagocytic function of microglia for remyelination is well known, the underlying metabolic pathways required for myelin debris clearance are poorly understood. Here, we show that cholesterol esterification in male mouse microglia/macrophages is a necessary adaptive response to myelin debris uptake and required for the generation of lipid droplets upon demyelinating injury. When lipid droplet biogenesis is defective, innate immune cells do not resolve, and the regenerative response fails. We found that triggering receptor expressed on myeloid cells 2 (TREM2)–deficient mice are unable to adapt to excess cholesterol exposure, form fewer lipid droplets, and build up endoplasmic reticulum (ER) stress. Alleviating ER stress in TREM2-deficient mice restores lipid droplet biogenesis and resolves the innate immune response. Thus, we conclude that TREM2-dependent formation of lipid droplets constitute a protective response required for remyelination to occur.

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. Microglia functionMicroglia are the only immune cells of the CNS and therefore the endogenous brain defence system.As such, they are responsible for CNS protection against diverse pathogenic factors (Kettenmann et al., 2011). Furthermore, microglia provide trophic support to neurons, remove apopto...