Abstract
Multiple sclerosis (MS) is an autoimmune, inflammatory disease of the central nervous system (CNS). We have measured the levels of over 20 non-esterified sterols in plasma and cerebrospinal fluid (CSF) from patients suffering from MS, inflammatory CNS disease, neurodegenerative disease and control patients. Analysis was performed following enzyme-assisted derivatisation by liquid chromatography–mass spectrometry (LC–MS) exploiting multistage fragmentation (MSn). We found increased concentrations of bile acid precursors in CSF from each of the disease states and that patients with inflammatory CNS disease classified as suspected autoimmune disease or of unknown aetiology also showed elevated concentrations of 25-hydroxycholestertol (25-HC, P < 0.05) in CSF. Cholesterol concentrations in CSF were not changed except for patients diagnosed with amyotrophic lateral sclerosis (P < 0.01) or pathogen-based infections of the CNS (P < 0.05) where they were elevated. In plasma, we found that 25-HC (P < 0.01), (25R)26-hydroxycholesterol ((25R)26-HC, P < 0.05) and 7α-hydroxy-3-oxocholest-4-enoic acid (7αH,3O-CA, P < 0.05) were reduced in relapsing-remitting MS (RRMS) patients compared to controls. The pattern of reduced plasma levels of 25-HC, (25R)26-HC and 7αH,3O-CA was unique to RRMS. In summary, in plasma, we find that the concentration of 25-HC in RRMS patients is significantly lower than in controls. This is consistent with the hypothesis that a lower propensity of macrophages to synthesise 25-HC will result in reduced negative feedback by 25-HC on IL-1 family cytokine production and exacerbated MS. In CSF, we find that the dominating metabolites reflect the acidic pathway of bile acid biosynthesis and the elevated levels of these in CNS disease is likely to reflect cholesterol release as a result of demyelination or neuronal death. 25-HC is elevated in patients with inflammatory CNS disease probably as a consequence of up-regulation of the type 1 interferon-stimulated gene cholesterol 25-hydroxylase in macrophages.
Highlights
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS)
We found that 25-HC (P < 0.01), (25R)26hydroxycholesterol ((25R)26-HC, P < 0.05) and 7α-hydroxy-3-oxocholest-4-enoic acid (7αH,3O-CA, P < 0.05) were reduced in relapsing-remitting MS (RRMS) patients compared to controls
In cerebrospinal fluid (CSF), we find that the dominating metabolites reflect the acidic pathway of bile acid biosynthesis and the elevated levels of these in CNS disease is likely to reflect cholesterol release as a result of demyelination or neuronal death. 25-HC is elevated in patients with inflammatory CNS disease probably as a consequence of upregulation of the type 1 interferon-stimulated gene cholesterol 25-hydroxylase in macrophages
Summary
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). Several disease-modifying drugs (DMDs) in addition to the first generation of injectable DMDs (IFN and glatiramer acetate) have been developed and licensed These include natalizumab, fingolimod, dimethyl fumarate, teriflunomide and alemtuzumab. As well as being essential metabolites controlling cholesterol levels and leading to the production of bile acids, oxysterols have been shown to modulate the immune system They, and their downstream metabolites, are ligands for nuclear hormone receptors such as the liver X receptors (LXRs), the farnesoid X receptor, the pregnane X receptor, the RAR-related orphan receptor γt (RORc2) [13,14,15,16], they modulate transcription in macrophages [17], and RORc2 activation plays a central role in the differentiation of Th17 cells [18]. The CSF data for the CP group has been published elsewhere [21]
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