WD-fed mice rapidly increased their weight to 34.76 g, on average, after 10 weeks of feeding, while mice on CD weighed 27.74 g on average ( Fig. The WD had a high fat content, in which 42% of the metabolizable energy came from fat, while the ratio was 13% in the CD ( Fig. To analyse the effects of diets on the regenerative response after demyelinating injury in mice, we fed 6-week-old C57BL/6J mice either a WD or control diet (CD) for 8 to 10 weeks 27 ( Fig. Western diet impairs lesion recovery after demyelinating injury As WD significantly alters macrophage metabolism in peripheral organs, we hypothesized that WD might influence the brain microenvironment, microglia metabolic functions and, ultimately, remyelination. Previous studies indicate that obesity may increase the risk of developing MS and accelerate the progression of MS towards increasing disability 25, 26. Apart from age, other factors that contribute to poor remyelination are unclear. With ageing, the activation, recruitment and differentiation of oligodendrocyte progenitors (OPCs) are altered, and the efficiency of microglia/macrophages to clear myelin debris also declines 8, 20– 24. One of the primary and best-understood reasons for the decline in remyelination efficiency is ageing. An improved understanding of disease mechanisms will enable the development of proregenerative therapies 5, 18, 19. However, in demyelinating diseases such as multiple sclerosis (MS), the capacity for remyelination is limited and varies between people 13– 17. Only when this clearance process is terminated does inflammation resolve and remyelination follow 11, 12. In addition, myelin is rich in cholesterol, which cannot be broken down, and therefore needs to be transferred from the phagocytes to the extracellular space onto lipoprotein particles. Myelin intake poses a challenge to phagocytes, as myelin is composed of tightly packed membrane stacks that are difficult to degrade 10. Following demyelination, microglia/macrophages proliferate and enter demyelinating lesions, where their prime task is to phagocytose, metabolize and clear damaged myelin 4– 9. To examine this question, we focused on a model of demyelinating injury that requires innate immune function for a regenerative response to occur. While obesity-induced inflammation in peripheral tissues is extensively studied, the mechanisms of WD-induced effects on microglia-mediated innate immunity in the central nervous system (CNS) are less clear. One feature associated with WD consumption is chronic systemic inflammation characterized by proinflammatory processes involving peripheral cells of the innate immune system 13. The transition of large parts of the world to a WD high in calories, fat and sugar represents one of the most profound environmental changes that has occurred over the past generations.
Thus, we have identified a druggable microglial immune checkpoint mechanism regulating the microglial response to injury that promotes remyelination. Blocking TGFβ or promoting triggering receptor expressed on myeloid cells 2 (TREM2) activity restores microglia responsiveness and myelin-debris clearance after demyelinating injury.
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. 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. 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.
Yet, the limiting factors responsible for poor CNS repair are only partially understood.
Proregenerative responses are required for the restoration of nervous-system functionality in demyelinating diseases such as multiple sclerosis (MS).
0 kommentar(er)
