Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS) with a complex pathogenesis. Lipids, abundant in axonal myelin sheaths, are believed to play a central role in disease progression; they have been implicated in both inflammatory demyelination and progressive neurodegeneration. Interestingly, research has suggested that lipids may also may be useful in diagnosing MS and monitoring disease progression. Furthermore, new drugs are being designed in which lipids are both targets of treatment and carriers of novel therapeutics.
Read more about MS etiology
Recently, in an article published in the International Journal of Molecular Sciences, researchers from the Medical University of South Carolina, in Charleston, South Carolina, reviewed the current understanding of lipid-related mechanisms as they pertain to MS. They highlight previous research on lipid-related mechanisms in MS pathogenesis and offers insights into the current usefulness of lipid biomarkers in predicting disease progression during active relapse and remission. Their article also describes novel therapeutic strategies in which lipid-based nanocarriers are used to improve the transport of targeted treatments across the blood-brain barrier (BBB).
Lipids in Acute MS Pathology
Damage to the CNS in MS is believed to be mediated by both an inflammatory demyelinating process and progressive neurodegeneration, according to the authors. The disease, comprising an active phase and a progressive/inactive phase, is thought to develop in genetically susceptible individuals exposed to an environmental trigger, such as infection, stress, or hormonal dysregulation.
Sphingolipids, a component of lipid bilayers with both functional and structural properties, have been implicated in MS disease activity. The article cites recent research that has identified alterations in sphingolipid pathways that may contribute to oligodendrocyte injury; this finding suggests that inappropriately regulated anti-inflammatory and pro-inflammatory lipids may play a key role in MS pathology. Ceramide lipids, in particular, have been implicated in oligodendrocyte damage and acute demyelination. The release of ceramide from stressed oligodendrocytes may “broadcast” cell death and trigger the autoimmune response that follows active demyelination, potentially functioning as a diagnostic and prognostic marker.
The article also cited several studies suggesting that cholesterol derivatives known as oxysterols are an important contributor to inflammatory demyelination in MS. Approximately 25% of the brain consists of cholesterol, a proportion significantly higher than that in other organs. In patients with MS, 24(S)-hydroxycholesterol can diffuse through a disrupted BBB, and its presence in the CNS indicates lipotoxic effects on CNS cells through alterations in cholesterol metabolism that affect the myelination process.
The authors note that oxysterols influence lipid synthesis by acting on transcription factors known as sterol regulatory element-binding proteins (SREBPs); these influence lipid homeostasis by regulating multiple genes involved in the synthesis and uptake of fatty acids, triglycerides, phospholipids, and cholesterol. In patients with MS, oxysterols produced through auto-oxidation, such as 7-ketocholesterol, appear to induce oligodendrocyte death.
These alterations in lipid metabolism may have diagnostic utility. The authors note that some of the alterations, such as overexpression of neuronal cholesterol 24-hydroxylase and increased cholesterol turnover, may result in abnormally high or low plasma levels of 24(S)-hydroxycholesterol and so might function as a stage-specific biomarker of disease activity.
New Insights Into MS Remission and Progression
The clinical presentation is often mild in the relapsing-remitting phase of MS and grows progressively more disabling in the progressive phase. The article highlights the role of the adaptive immune response in the relapsing-remitting phase, whereas the innate immune system appears to drive disease progression in the progressive phase. The researchers posit invariant natural killer (iNKT) cells as a bridge between adaptive and innate immunity—the phase largely characterized by lymphocyte anergy that results in MS remission. It is hoped that a better understanding of the molecular basis of the observed anergy of iNKT cells during CNS autoimmunity will lead to improved treatment options, according to the study authors.
Read more about MS prognosis
In the progressive phase of MS, neurodegeneration outpaces inflammatory demyelination, resulting in a gradually expanding accumulation of CNS injuries such as active/inactive chronic MS plaques and smoldering lesions. This phase of the disease is associated with overactive microglia, which release proinflammatory cytokines and proteolytic enzymes, as well as the through-production of reactive oxidative stress (ROS) and nitric oxide. Oxidative stress is particularly damaging to the CNS, and an increased level of biomarkers of oxidative stress, such as total hydroxy-oxtadecanoic acid, has been observed in patients with MS. The authors also note that increased levels of lipid peroxidation products, such as 4-hydroxy-2-nonenal, have been found to be detrimental to CNS cells and BBB integrity in patients with MS.
Biomarkers and Targets of Therapeutics
A separate review published earlier this year in Cellular and Molecular Life Sciences highlighted the difficulties encountered in diagnosing MS. The authors note, “The misdiagnosis of MS is a persistent problem as there is no definitive test, which poses a considerable clinical and psychosocial burden for patients and medical workers. This accentuates the urgent need for MS-specific biomarkers with diagnostic, prognostic and therapeutic potential.”
The researchers in South Carolina note that functional analysis of the lipid alterations observed in MS progression has identified associations indicating that lipids may be relevant biomarkers of disease activity. Serum levels of 24(S)-hydroxycholesterol were found to correlate negatively with normalized measurements of brain volume on magnetic resonance imaging (MRI). Levels of C20:0-HexCer have been linked to global brain atrophy in primary progressive MS. These findings suggest that lipids may play an important role in predicting and monitoring the course of MS, particularly in the progressive stage of the illness. The study authors note a pressing need for ways to predict and monitor MS progression.
Targeted therapies (eg, sphingosine 1-phosphate receptor [S1PR] modulators such as fingolimod) have been shown to limit the migration of autoreactive T cells into the CNS and contribute to autoreactive T-cell apoptosis, thus reducing relapse rates and decreasing brain atrophy and the formation of new CNS lesions on MRI. The review mentions several S1PR1 and S1PR5 modulators, including ozanimod and siponimod, that appear to reduce disease burden and promote axonal remyelination. Furthermore, many advantages have been shown for using lipid-based nanocarriers to transport CNS-based therapies through the BBB to improve therapeutic delivery.
As the authors note, “These insights highlight the potential usefulness of lipid molecules as biomarkers in the prediction or monitoring of the disease course of MS, particularly in its progressive stage, still insufficiently addressed. Furthermore, the reviewed research data raise hope for new, effective, and stage-specific treatment options, involving lipids as targets or carriers of therapeutic agents. These putative diagnostic and therapeutic implications of the novel findings encourage further development of the lipid-based investigations.”
Podbielska M, O’Keefe J, Pokryszko-Dragon A. New insights into multiple sclerosis mechanisms: lipids on the track to control inflammation and neurodegeneration. Int J Mol Sci. 2021;22(14):7319. doi:10.3390/ijms22147319
Podbielska M, O’Keefe J, Hogan E. Autoimmunity in multiple sclerosis: role of sphingolipids, invariant NKT cells and other immune elements in control of inflammation and neurodegeneration. J Neurol Sci. 2018;385:198-214. doi:10.1016/j.jns.2017.12.022