Local cholesterol metabolism orchestrates remyelination

The myelin sheath is a structure of layered cholesterol-rich membranes that extend from the plasma membrane of oligodendrocytes. Myelin membranes wrap around and insulate neuronal axons to facilitate rapid impulse conduction.Myelination starts during embryogenesis and continues postnatally. Myelin integrity is crucial to maintain CNS function. As cholesterol import into the CNS is very limited, developmental myelination is driven by local synthesis, predominantly in oligodendrocytes.Perturbation of CNS cholesterol metabolism is often linked to neurological disease, including the most common inflammatory neurological disorder, multiple sclerosis (MS). MS is characterized by focal loss of myelin, referred to as demyelinated lesions.Repair of lesions is linked to local cholesterol metabolism, involving the cooperation between CNS cell types. Endogenous repair strategies differ between the acute and chronic phases of myelin disease, and their efficacy attenuates with disease chronicity.Future therapeutic interventions might consider targeting critical steps of CNS cholesterol metabolism to support remyelination. Cholesterol is an essential component of all cell membranes and particularly enriched in myelin membranes. Myelin membranes are a major target of immune attacks in the chronic neurological disorder multiple sclerosis (MS). During demyelinating insults, cholesterol is released from damaged myelin, increasing local levels of this unique lipid and impeding tissue regeneration. Here, we summarize the current knowledge of cholesterol-dependent processes during demyelination and remyelination, emphasizing cell type-specific responses. We discuss cellular lipid/cholesterol metabolism during early and late disease phases and highlight the concept of lipid-based pharmacological interventions. We propose that knowledge of the interplay between cell type-specific cholesterol handling, inflammation, and blood–brain barrier (BBB) integrity will unravel disease processes and facilitate development of strategies for therapies to promote remyelination. Cholesterol is an essential component of all cell membranes and particularly enriched in myelin membranes. Myelin membranes are a major target of immune attacks in the chronic neurological disorder multiple sclerosis (MS). During demyelinating insults, cholesterol is released from damaged myelin, increasing local levels of this unique lipid and impeding tissue regeneration. Here, we summarize the current knowledge of cholesterol-dependent processes during demyelination and remyelination, emphasizing cell type-specific responses. We discuss cellular lipid/cholesterol metabolism during early and late disease phases and highlight the concept of lipid-based pharmacological interventions. We propose that knowledge of the interplay between cell type-specific cholesterol handling, inflammation, and blood–brain barrier (BBB) integrity will unravel disease processes and facilitate development of strategies for therapies to promote remyelination. The primary origin of brain cholesterol is de novo synthesis, likely involving all cell types of the CNS. The entry of peripheral cholesterol to the brain is prevented by the shielding properties of the BBB. In the adult CNS, the majority (~70–80%) of cholesterol is located in lipid-rich myelin membranes [1.Dietschy J.M. Central nervous system: cholesterol turnover, brain development and neurodegeneration.Biol. Chem. 2009; 390: 287-293Google Scholar,2.Björkhem I. et al.Genetic connections between neurological disorders and cholesterol metabolism.J. Lipid Res. 2010; 51: 2489-2503Google Scholar]. As a multilayered stack of oligodendrocyte membranes that wrap around neuronal processes, myelin insulates axons to effect fast nerve conduction. During early postnatal development, oligodendrocyte precursor cells (OPCs) differentiate to mature oligodendrocytes. This involves crosstalk between a plethora of stage-specific transcription factors [e.g., Olig1/2, SOX10, Myrf, retinoid X receptors (RXRs)], signaling pathways [e.g., mammalian target of rapamycin (mTOR), Wnt/β-catenin, Sonic hedgehog, fibroblast growth factors (FGFs), peroxisome proliferator-activated receptors (PPARs)], and increased cholesterol synthesis [3.Zhao C. et al.Dual regulatory switch through interactions of Tcf7l2/Tcf4 with stage-specific partners propels oligodendroglial maturation.Nat. Commun. 2016; 7: 10883Google Scholar, 4.Fancy S.P.J. et al.Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS.Genes Dev. 2009; 23: 1571-1585Google Scholar, 5.Emery B. Lu Q.R. 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Cholesterol availability is rate-limiting for myelination, and the majority of the cholesterol required for myelination is synthesized by oligodendrocytes themselves [8.Saher G. et al.High cholesterol level is essential for myelin membrane growth.Nat. Neurosci. 2005; 8: 468-475Google Scholar]. In addition, astrocyte-derived cholesterol complements oligodendrocyte-synthesized cholesterol by transfer of apolipoprotein E (ApoE)-containing lipoproteins, the transport vehicles for cholesterol and lipids in the CNS [9.Camargo N. et al.Oligodendroglial myelination requires astrocyte-derived lipids.PLoS Biol. 2017; 15e1002605Google Scholar]. After completion of developmental myelination, oligodendrocytes continue low-rate cholesterol synthesis for myelin maintenance. In adults, steady-state brain cholesterol production is chiefly attributed to astrocytes that supply neighboring neurons and glial cells to meet their cellular demands [10.Wang H. Eckel R.H. 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Accordingly, in adult mice, genetically induced loss of cholesterol synthesis in one CNS cell type, that is, astrocytes, oligodendrocytes, neurons, microglia, or endothelial cells, is efficiently compensated by enhanced transport from other cell types [8.Saher G. et al.High cholesterol level is essential for myelin membrane growth.Nat. Neurosci. 2005; 8: 468-475Google Scholar,9.Camargo N. et al.Oligodendroglial myelination requires astrocyte-derived lipids.PLoS Biol. 2017; 15e1002605Google Scholar,13.Berghoff S.A. et al.Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.Nat. Neurosci. 2021; 24: 47-60Google Scholar,14.Fünfschilling U. et al.Critical time window of neuronal cholesterol synthesis during neurite outgrowth.J. Neurosci. 2012; 32: 7632-7645Google Scholar], highlighting the flexibility of CNS cholesterol metabolism. Of note, cholesterol synthesis rates decrease in the aging brain [15.de la Fuente A.G. et al.Changes in the oligodendrocyte progenitor cell proteome with ageing.Mol. Cell. Proteomics. 2020; 19: 1281-1302Google Scholar, 16.Thelen K.M. et al.Cholesterol synthesis rate in human hippocampus declines with aging.Neurosci. Lett. 2006; 403: 15-19Google Scholar, 17.Boisvert M.M. et al.The aging astrocyte transcriptome from multiple regions of the mouse brain.Cell Rep. 2018; 22: 269-285Google Scholar]. Together with dysregulation of metabolic pathways, increasingly compromised functions of microglia/macrophages, and elevated inflammatory processes collectively called ‘inflammaging’, perturbed cholesterol homeostasis likely contributes to aging and its risk to develop neurodegenerative disease [18.Franceschi C. et al.Inflammaging: a new immune-metabolic viewpoint for age-related diseases.Nat. Rev. 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Especially, etiologies affecting myelin membranes such as MS are linked to dysregulated cholesterol homeostasis [23.Berghoff S.A. et al.Dietary cholesterol promotes repair of demyelinated lesions in the adult brain.Nat. Commun. 2017; 8: 14241Google Scholar, 24.Saher G. et al.Therapy of Pelizaeus-Merzbacher disease in mice by feeding a cholesterol-enriched diet.Nat. Med. 2012; 18: 1130-1135Google Scholar, 25.Saher G. Stumpf S.K. Cholesterol in myelin biogenesis and hypomyelinating disorders.Biochim. Biophys. Acta. 2015; 1851: 1083-1094Google Scholar]. This review article focuses on the current knowledge of the relevance of cell type-specific cholesterol metabolism to demyelinating disease. We propose different disease mechanisms related to cholesterol metabolism during acute and chronic demyelination. While cholesterol recycling processes dominate repair after acute demyelination, newly synthesized cholesterol drives remyelination in chronic disease. Moreover, the analysis of cell type-specific defects in cholesterol metabolism has revealed the importance and the limits of cholesterol transport between the cells in the brain. The understanding of disease mechanisms in models of myelin disease may lead to therapeutic advances. In demyelinating diseases such as MS (Box 1), damaged myelin is cleared by phagocytes and new myelin sheaths are generated from existing or newly differentiated oligodendrocytes. Demyelination/remyelination events likely occur also during the prodromal disease phase in MS, before manifestation of symptoms, as well as in healthy individuals. In both cases, endogenous repair efficiently restores myelin sheaths [26.Filippi M. et al.Multiple sclerosis.Nat. Rev. Dis. Primers. 2018; 4: 43Google Scholar,27.Heß K. et al.Lesion stage-dependent causes for impaired remyelination in MS.Acta Neuropathol. 2020; 140: 359-375Google Scholar]. However, with disease progression and chronicity, these regenerative processes exhaust and the failure to remyelinate ultimately leads to axonal damage, preventing clinical recovery [27.Heß K. et al.Lesion stage-dependent causes for impaired remyelination in MS.Acta Neuropathol. 2020; 140: 359-375Google Scholar,28.Franklin R.J.M. et al.Revisiting remyelination: towards a consensus on the regeneration of CNS myelin.Semin. Cell Dev. Biol. 2021; 116: 3-9Google Scholar].Box 1Multiple sclerosisMS is the most common inflammatory, demyelinating neurodegenerative disease of the CNS worldwide. The pathological hallmark of this chronic disease is demyelinating lesions driven by impaired immune regulation. Concordantly, peripheral immune cells such as B and T lymphocytes as well as microglia, the resident immune cells of the CNS, have been linked to expression of MS risk variant genes that were discovered by genome-wide association studies [119.Gresle M.M. et al.Multiple sclerosis risk variants regulate gene expression in innate and adaptive immune cells.Life Sci. Alliance. 2020; 3e202000650Google Scholar,120.International Multiple Sclerosis Genetics Consortium Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility.Science. 2019; 365eaav7188Google Scholar]. MS typically manifests in young adults as clinically isolated syndrome, but is likely preceded by subthreshold demyelinating events. Pathophysiological and clinical presentations are highly heterogeneous. In most cases, in early disease, autoinflammatory episodes with neurological symptoms (relapses) alternate with remission phases. However, lesion development and regeneration can occur in parallel in MS patients. Complete repair of demyelinated lesions might be possible in early disease. However, disease chronicity, further aggravated by aging and environmental and/or genetic factors, persistently damages the CNS, leading to progressive neurological disability.The cause of MS is unknown and likely multifactorial. Disease mechanisms differ in the acute and chronic disease phases, but also share several common features. Autoreactive T lymphocytes and other effector immune cells enter the brain parenchyma by diapedesis across the BBB and attack myelin membranes and/or neurons. Inflammatory mediators contribute to pathogenesis by triggering myelin degeneration. Phagocytes, mainly CNS microglia and macrophages, mediate removal of myelin debris. In addition, inflammatory mediators perturb CNS homeostasis and locally compromise the BBB, allowing the entry of blood-borne factors.The current MS treatments mainly target neuroinflammation and efficiently alleviate symptoms as well as reduce the rate of demyelinating episodes but do not cure this devastating disease. There is an urgent need for medications that support myelin repair. Several such compounds are currently in development and might in combination with immunomodulators change the landscape of MS therapy in the future. MS is the most common inflammatory, demyelinating neurodegenerative disease of the CNS worldwide. The pathological hallmark of this chronic disease is demyelinating lesions driven by impaired immune regulation. Concordantly, peripheral immune cells such as B and T lymphocytes as well as microglia, the resident immune cells of the CNS, have been linked to expression of MS risk variant genes that were discovered by genome-wide association studies [119.Gresle M.M. et al.Multiple sclerosis risk variants regulate gene expression in innate and adaptive immune cells.Life Sci. Alliance. 2020; 3e202000650Google Scholar,120.International Multiple Sclerosis Genetics Consortium Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility.Science. 2019; 365eaav7188Google Scholar]. MS typically manifests in young adults as clinically isolated syndrome, but is likely preceded by subthreshold demyelinating events. Pathophysiological and clinical presentations are highly heterogeneous. In most cases, in early disease, autoinflammatory episodes with neurological symptoms (relapses) alternate with remission phases. However, lesion development and regeneration can occur in parallel in MS patients. Complete repair of demyelinated lesions might be possible in early disease. However, disease chronicity, further aggravated by aging and environmental and/or genetic factors, persistently damages the CNS, leading to progressive neurological disability. The cause of MS is unknown and likely multifactorial. Disease mechanisms differ in the acute and chronic disease phases, but also share several common features. Autoreactive T lymphocytes and other effector immune cells enter the brain parenchyma by diapedesis across the BBB and attack myelin membranes and/or neurons. Inflammatory mediators contribute to pathogenesis by triggering myelin degeneration. Phagocytes, mainly CNS microglia and macrophages, mediate removal of myelin debris. In addition, inflammatory mediators perturb CNS homeostasis and locally compromise the BBB, allowing the entry of blood-borne factors. The current MS treatments mainly target neuroinflammation and efficiently alleviate symptoms as well as reduce the rate of demyelinating episodes but do not cure this devastating disease. There is an urgent need for medications that support myelin repair. Several such compounds are currently in development and might in combination with immunomodulators change the landscape of MS therapy in the future. In MS patients, new lesions can develop regardless of the discrete relapsing and remitting neurological events. Moreover, the development of a new lesion can coincide with the repair of another lesion. Therefore, rodent MS models with induced causality and spatiotemporal predictability of pathology have been instrumental in exploring distinct phases of demyelination and remyelination [29.Kipp M. et al.Multiple sclerosis animal models: a clinical and histopathological perspective.Brain Pathol. 2017; 27: 123-137Google Scholar,30.Titus H.E. et al.Pre-clinical and clinical implications of "inside-out" vs. "outside-in" paradigms in multiple sclerosis etiopathogenesis.Front. Cell. Neurosci. 2020; 14599717Google Scholar]. In experimental animals, a cycle of inflammatory demyelination and remyelination essentially involves sequential phases of phagocyte activation, myelin clearance, resolution of the inflammation, and establishment of a local proregenerative microenvironment [31.Plemel J.R. et al.Myelin inhibits oligodendroglial maturation and regulates oligodendrocytic transcription factor expression.Glia. 2013; 61: 1471-1487Google Scholar]. Activation of phagocytes precedes phagocytosis of myelin debris, involving the TAM receptor tyrosine kinases (Tyro3, Axl, MerTK) and triggering receptor expressed on myeloid cells 2 (TREM2) that are part of the disease-associated microglia (DAM) program [32.Lampron A. et al.Inefficient clearance of myelin debris by microglia impairs remyelinating processes.J. Exp. 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Microglia/macrophages show the highest phagocytic activity, but also astrocytes contribute to myelin clearance [38.Rawji K.S. et al.The role of astrocytes in remyelination.Trends Neurosci. 2020; 43: 596-607Google Scholar]. The internalization and turnover of myelin lipids and proteins in these cells, which involve autophagic processes [39.Robichaud S. et al.Identification of novel lipid droplet factors that regulate lipophagy and cholesterol efflux in macrophage foam cells.Autophagy. 2021; 17: 3671-3689Google Scholar, 40.Rickman A.D. et al.Dying by fire: noncanonical functions of autophagy proteins in neuroinflammation and neurodegeneration.Neural Regen. Res. 2022; 17: 246-250Google Scholar, 41.Nutma E. et al.Autophagy in white matter disorders of the CNS: mechanisms and therapeutic opportunities.J. Pathol. 2021; 253: 133-147Google Scholar, 42.Berglund R. et al.Microglial autophagy-associated phagocytosis is essential for recovery from neuroinflammation.Sci. 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Cholesterol is a major and essential component of myelin membranes. As mammals cannot degrade it, the cholesterol from degenerating myelin membranes is either locally recycled, as described previously, or exported from the brain. Experimental interference at distinct levels of cholesterol/lipid metabolism has unraveled the intimate interplay between myelin membrane destruction, intracellular cholesterol/lipid trafficking, efflux, and recycling, as well as the inflammatory profile of phagocytes [46.Cole D.C. et al.Loss of APOBEC1 RNA-editing function in microglia exacerbates age-related CNS pathophysiology.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 13272-13277Google Scholar, 47.Bogie J.F.J. et al.Stearoyl-CoA desaturase-1 impairs the reparative properties of macrophages and microglia in the brain.J. Exp. Med. 2020; 217e20191660Google Scholar, 48.Colombo A. et al.Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia.Nat. Commun. 2021; 12: 1158Google Scholar]. Based on these lines of evidence, we hypothesize that cholesterol metabolism critically influences repair of demyelinated lesions. However, the particular roles of this metabolic pathway in the different disease phases differ. While repair of acute lesions is driven by cholesterol recycling, remyelination after chronic demyelination requires local cholesterol synthesis, as outlined later (Figure 1). The uptake of cholesterol from degenerating myelin increases cellular cholesterol levels in phagocytes, which in turn inhibits their rate of cholesterol synthesis. Feedback regulation of cholesterol synthesis occurs at transcriptional, translational, and post-translational levels. It involves sterol regulatory element-binding protein 2 (SREBP2), the master transcriptional regulator, as well as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and squalene monooxygenase, the rate-limiting enzymes of this pathway [49.Luo J. et al.Mechanisms and regulation of cholesterol homeostasis.Nat. Rev. Mol. Cell Biol. 2020; 21: 225-245Google Scholar]. Excess intracellular cholesterol can also enhance the synthesis of oxysterols [50.Dang E.V. et al.Oxysterol restraint of cholesterol synthesis prevents AIM2 inflammasome activation.Cell. 2017; 171: 1057-1071.e11Google Scholar,51.Viaud M. et al.Lysosomal cholesterol hydrolysis couples efferocytosis to anti-inflammatory oxysterol production.Circ. Res. 2018; 122: 1369-1384Google Scholar]. By contrast, uptake of cholesterol from myelin debris in the proinflammatory environment of actively demyelinating lesions increases the sterol synthesis pathway, occurring exclusively in phagocytes [13.Berghoff S.A. et al.Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.Nat. Neurosci. 2021; 24: 47-60Google Scholar]. During active demyelination at the edge of expanding lesions, phagocytes contain myelin debris including lipids but, in contrast to chronic lesions, only rarely appear lipid-laden and foamy [52.Prineas J.W. Parratt J.D.E. Multiple sclerosis: microglia, monocytes, and macrophage-mediated demyelination.J. Neuropathol. Exp. Neurol. 2021; 80: 975-996Google Scholar]. This is notable given the high amount of released lipids from first-time degenerating myelin in white matter areas and suggests instantaneous recycling and export of internalized cholesterol to facilitate the rapid functional repair of demyelinated lesions in early disease. Likely recycled cholesterol, presumably contained in lipoproteins, is transferred to astrocytes, oligodendrocytes, endothelial cells, and neurons, where it leads to local downregulation of cholesterol synthesis and increased synthesis of several oxysterols [13.Berghoff S.A. et al.Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.Nat. Neurosci. 2021; 24: 47-60Google Scholar,53.Itoh N. et al.Cell-specific and region-specific transcriptomics in the multiple sclerosis model: focus on astrocytes.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: E302-E309Google Scholar, 54.Voskuhl R.R. et al.Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis.Proc. Natl. Acad. Sci. U. S. A. 2019; 116: 10130-10139Google Scholar, 55.Berghoff S.A. et al.Neuronal cholesterol synthesis is essential for repair of chronically demyelinated lesions in mice.Cell Rep. 2021; 37109889Google Scholar]. Remarkably, functional CNS phagocyte sterol synthesis following myelin uptake mediates cholesterol efflux and limits inflammation [13.Berghoff S.A. et al.Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.Nat. Neurosci. 2021; 24: 47-60Google Scholar]. Similarly, phagocytosing macrophages in atherosclerosis increase reverse cholesterol transport and suppress inflammatory responses [56.Spann N.J. et al.Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses.Cell. 2012; 151: 138-152Google Scholar]. By limiting enzymatic activity of the terminal cholesterol synthesis enzyme 24-dehydrocholesterol reductase (Dhcr24) by transcriptional downregulation, lipid-internalizing phagocytes synthesize the immediate cholesterol precursor, desmosterol (Figure 1). By its liver X receptor (LXR)-activating function (Box 2), desmosterol induces expression of cholesterol efflux genes such as Abca1 and facilitates the resolution of the proinflammatory phenotype [13.Berghoff S.A. et al.Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.Nat. Neurosci. 2021; 24: 47-60Google Scholar,56.Spann N.J. et al.Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses.Cell. 2012; 151: 138-152Google Scholar], likely by direct and indirect mechanisms [57.Thomas D.G. et al.LXR suppresses inflammatory gene expression and neutrophil migration through cis-repression and cholesterol efflux.Cell Rep. 2018; 25: 3774-3785.e4Google Scholar,58.Korner A. et al.Inhibition of Δ24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution.Proc. Natl. Acad. Sci. U. S. A. 2019; 116: 20623-20634Google Scholar]. Conversely, genetic loss of sterol synthesis in microglia leads to the appearance of proinflammatory, lipid-loaded foamy phagocytes, due to downregulated efflux transporters [13.Berghoff S.A. et al.Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.Nat. Neurosci. 2021; 24: 47-60Google Scholar]. In active MS lesions, DHCR24 is downregulated, desmosterol levels are increased, and the LXR signaling pathway is activated [13.Berghoff S.A. et al.Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.Nat. Neurosci. 2021; 24: 47-60Google Scholar,59.Hendrickx D.A.E. et al.Gene expression profiling of multiple sclerosis pathology identifies early patterns of demyelination surrounding chronic active lesions.Front. Immunol. 2017; 8: 1810Google Scholar,60.Mailleux J. et al.Active liver X receptor signaling in phagocytes in multiple sclerosis lesions.Mult. Scler. 2018; 24: 279-289Google Scholar]. Together with the observation that mutation in the LXRα [nuclear receptor subfamily 1 group H member 3 (NR1H3)] gene leads to increased disease risk [61.Wang Z. et al.Nuclear receptor NR1H3 in familial multiple sclerosis.Neuron. 2016; 92: 555Google Scholar], these findings point to a pivotal role for LXR signaling in phagocyte-mediated MS lesion repair. In addition to desmosterol, oxysterols are potent endogenous LXR agonists that contribute to LXR activation. As oxysterols can readily pass the BBB, they might serve as candidate disease biomarkers [62.Zmyslowski A. Szterk A. Oxysterols as a biomarker in diseases.Clin. Chim. Acta. 2019; 491: 103-113Google Scholar]. It remains debated whether the rate of myelin degradation depends on the presence of a proinflammatory environment during demyelination. It is possible that proinflammatory mediators serve to maintain desmosterol synthesis in phagocytes. In this model, the resulting activation of LXR signaling then prevents intracellular lipid accumulation and facilitates efficient lipid/cholesterol recycling in early MS lesions.Box 2LXR signalingLXRs are transcription factors of the nuclear receptor family. The NR1H3 and NR1H2 genes encode the two isoforms of LXR, LXRα and LXRβ. L