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...

Microglial cells are highly dynamic cells with processes continuously moving to survey the surrounding territory. Microglia possess a broad variety of surface receptors and subtle changes in their microenvironment cause microglial cell processes to extend, retract, and interact with neuronal synaptic contacts. When the nervous system is disturbed, microglia activate, proliferate, and migrate to sites of injury in response to alert signals. Released nucleotides like ATP and UTP are among the wide range of molecules promoting microglial activation and guiding their migration and phagocytic function. The increased concentration of nucleotides in the extracellular space could be involved in the microglial wrapping found around injured neurons in various pathological conditions, especially after peripheral axotomy. Microglial wrappings isolate injured neurons from synaptic inputs and facilitate the molecular dialog between endangered or injured neurons and activated microglia. Astrocytes may also participate in neuronal ensheathment. Degradation of ATP by microglial ecto-nucleotidases and the expression of various purine receptors might be decisive in regulating the function of enwrapping glial cells and in determining the fate of damaged neurons, which may die or may regenerate their axons and survive.

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Axonal degeneration determines the clinical outcome of multiple sclerosis (MS), and is thought to result from exposure of denuded axons to immune-mediated damage. We challenge this view after finding in MS and its mouse models that myelin itself increases the risk of axons to degenerate under inflammatory conditions. We propose a model for demyelinating diseases in which for axons that remain myelinated, and thus shielded from the extracellular milieu, dependence from oligodendroglial support turns fatal in an autoimmune disease environment.

Highlights d Lipid and fatty acid abundance is specifically altered during de-and remyelination d Reduction of pro-and anti-inflammatory lipid mediators impairs lesion recovery d DHA supplementation fosters phagocyte decline and oligodendrocyte generation d n-3 fatty acid supplementation may be a strategy to promote remyelination

Axonal degeneration determines the clinical outcome of multiple sclerosis and is thought to result from exposure of denuded axons to immune-mediated damage. Therefore, myelin is widely considered to be a protective structure for axons in multiple sclerosis. Myelinated axons also depend on oligodendrocytes, which provide metabolic and structural support to the axonal compartment. Given that axonal pathology in multiple sclerosis is already visible at early disease stages, before overt demyelination, we reasoned that autoimmune inflammation may disrupt oligodendroglial support mechanisms and hence primarily affect axons insulated by myelin. Here, we studied axonal pathology as a function of myelination in human multiple sclerosis and mouse models of autoimmune encephalomyelitis with genetically altered myelination. We demonstrate that myelin ensheathment itself becomes detrimental for axonal survival and increases the risk of axons degenerating in an autoimmune environment. This challenges the view of myelin as a solely protective structure and suggests that axonal dependence on oligodendroglial support can become fatal when myelin is under inflammatory attack.