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

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. 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...

Proteomic and lipidomic profiling of demyelinating lesions identifies fatty acids as modulators in lesion recovery

“…The density of IBA1 + phagocytes was higher in ALOX15-deficient mice compared to control ( Figures 3 D and 3H). In addition, KO mice showed an increase of phagocyte-associated myelin debris and increased crystal formation ( Figures 3 F, 3I, and 3J), which is associated with dysfunctional cholesterol clearance, persisting inflammation, and impaired remyelination ( Bosch-Queralt et al., 2021 ; Cantuti-Castelvetri et al., 2018 ). In accordance, the percentage of CC1 + OLIG2 + mature oligodendrocytes was slightly reduced in ALOX15-deficient mice, while the total densities of OLIG2 + oligodendrocyte lineage cells were equal ( Figures 3 G, 3K, and S3 C).…”

“…Ideally, the inflammatory innate response is self-limiting, and the phagocytic infiltrate declines over time. With increasing age or obesity, however, the response can become maladaptive and impede remyelination ( Bosch-Queralt et al., 2021 ; Cantuti-Castelvetri et al., 2018 ; Chiurchiù et al., 2018 ). Using a systems biology approach combining proteomics and lipidomics, we characterized lipid pathways and lipid mediators that are upregulated in demyelinating lesions.…”

“…The regenerative response requires the activation of the innate immune system, starting with a mounting microglia/macrophage infiltration that subsequently resolves in a precisely controlled manner ( Domingues et al., 2016 ; Lloyd and Miron, 2019 ; McMurran et al., 2016 ). While innate immune cells play an important role in phagocytosing myelin debris and producing pro-regenerative factors, maladaptive and prolonged immune reactions can lead to chronic or uncontrolled inflammation, which impedes repair ( Bosch-Queralt et al., 2021 ; Cantuti-Castelvetri et al., 2018 ; Cunha et al., 2020 ; Dong et al., 2021 ; Kotter et al., 2005 , 2006 ; Miron et al., 2013 ; Gouna et al, 2021 ; Shen et al, 2021 ). Thus, identifying the factors that control innate immune activation and inflammation resolution is essential for our understanding of remyelination.…”

Microglial Lipid Biology in the Hypothalamic Regulation of Metabolic Homeostasis

“…Indeed, both PD patients and experimental animal models of PD exhibit abnormal lipid accumulation in dopaminergic neurons and their surrounding microglia, but have a reduced lipid load in adjacent astrocytes. One recent study found that a Western diet impairs recovery from demyelinating injuries, by inhibiting microglial phagocytosis and clearance of lipid debris ( 25 ). Another study found that in the setting of demyelination, microglia synthesize desmosterol, the immediate cholesterol precursor and liver X receptor (LXR) agonist, and that microglial sterol synthesis is essential for efficient remyelination ( 26 ).…”

Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology

“…A number of agonistic anti-TREM2 antibodies were recently developed (Cheng et al, 2018;Cignarella et al, 2020;Ellwanger et al, 2021;Fassler et al, 2021;Price et al, 2020;Schlepckow et al, 2020;Wang et al, 2020), which either enhance cell-surface levels of signaling competent TREM2 by blocking TREM2 shedding and/or crosslink TREM2 receptors to stimulate downstream signaling via Syk phosphorylation. In preclinical studies these antibodies boost protective functions of microglia as shown by enhanced amyloid ßpeptide (A ß) and myelin clearance, reduced amyloid plaque load, improved memory in models of amyloidosis, and support of axon regeneration and remyelination in models of demyelinating disorders such as multiple sclerosis (Bosch-Queralt et al, 2021;Cheng et al, 2018;Cignarella et al, 2020;Ellwanger et al, 2021;Fassler et al, 2021;Lewcock et al, 2020;Price et al, 2020;Schlepckow et al, 2020;Wang et al, 2020).…”