Oxysterols regulate encephalitogenic CD4+ T cell trafficking during central nervous system autoimmunity

Chalmin, Fanny; Rochemont, Viviane; Lippens, Carla; Clottu, Aurélie; Sailer, Andreas W.; Merkler, Doron; Hugues, Stéphanie; Pot, Caroline

doi:10.1016/j.jaut.2014.10.001

Cited by 81 publications

(110 citation statements)

References 36 publications

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“…Oxysterols inhibit EAE by down-regulating IL-17 production and suppressing Th17 cells 23 . Dendritic cells produce cholesterol 27 hydroxylase during EAE 25 . Thus the reductions in 24HC, 27HC and 7αHC levels and the increases in 7KC levels that we observed could potentially contribute to pathophysiological immune effects in MS.…”

Section: Discussionmentioning

confidence: 99%

Interdependence of oxysterols with cholesterol profiles in multiple sclerosis

et al. 2016

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Purpose To investigate levels of oxysterols in healthy control (HC) and multiple sclerosis (MS) patients and their inter-dependence with demographic, clinical characteristics and cholesterol biomarkers. Methods This study included 550 subjects (203 HC, 221 relapsing-remitting MS (RR-MS), 126 progressive MS (P-MS)). A complete lipid profile including total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), apolipoproteins (Apo) A1, A2, B, E, C-reactive protein (CRP), 24-hydroxycholesterol (24HC), 25HC, 27HC, 7αHC and 7-ketocholesterol (7KC) was obtained. Lipoprotein particle sizing by H1 NMR was available for 432 subjects. Results The levels of 24HC, 27HC, and 7αHC (all p < 0.015) were lower in MS compared to HC, and 7KC was higher in P-MS compared to RR-MS (p < 0.001). TC, LDL-C and ApoB were associated with higher levels of all oxysterols (all p < 0.05) in HC. In MS, LDL-C was associated with higher levels of 24HC, 25HC, 7KC, and 7αHC (all p < 0.05), while TC and ApoB were associated with increased levels of all oxysterols (all p < 0.005). Conclusions The findings of lower 24HC, 27HC and 7αHC in MS compared to HC and higher 7KC in P-MS compared to RR-MS indicate that the oxysterol network is disrupted in MS.

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Section: Discussionmentioning

confidence: 99%

Interdependence of oxysterols with cholesterol profiles in multiple sclerosis

et al. 2016

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“…Cholesterol synthesis and transport in oligodendrocytes is essential for optimal myelination and remyelination, and defective homeostasis has been implicated in several neurological diseases, including MS (Chalmin et al, 2015;Leoni and Caccia, 2011).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

Wang¹,

Sadovnick²,

Traboulsee³

et al. 2016

Neuron

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SUMMARYMultiple sclerosis (MS) is an inflammatory disease characterized by myelin loss and neuronal dysfunction. Despite the aggregation observed in some families, pathogenic mutations have remained elusive. In this study we describe the identification of NR1H3 p.Arg415Gln in seven MS patients from two multi-incident families presenting severe and progressive disease, with an average age at onset of 34 years. Additionally, association analysis of common variants in NR1H3 identified rs2279238 conferring a 1.35-fold increased risk of developing progressive MS. The p.Arg415Gln position is highly conserved in orthologs and paralogs, and disrupts NR1H3 heterodimerization and transcriptional activation of target genes. Protein expression analysis revealed that mutant NR1H3 (LXRA) alters gene expression profiles, suggesting a disruption in transcriptional regulation as one of the mechanisms underlying MS pathogenesis. Our study indicates that pharmacological activation of LXRA or its targets may lead to effective treatments for the highly debilitating and currently untreatable progressive phase of MS.

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“…Accumulating evidence underscores the capability of perturbed cholesterol homeostasis to modulate inflammation and potentially promotes autoimmune disease 27, 28 . Therefore, we next analyzed the expression pattern of key molecules involved in biosynthesis (HMGCR), recycling (ApoE), and degradation (CYP46A1) of cholesterol in the course of EAE using real-time PCR and Western blot analysis (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Myelin taken up by macrophages is degraded generating oxysterols, which could have a role in promoting autoimmunity as signal molecules 27 . Additionally, cholesterol may promote inflammatory mediators production by macrophages 28 , generating vicious cycle of inflammation.…”

Section: Introductionmentioning

confidence: 99%

Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord

Lavrnja

Smiljanić

Savić

et al. 2017

Sci Rep

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Increased evidence suggests that dysregulation of cholesterol metabolism may be a key event contributing to progression of multiple sclerosis (MS). Using an experimental autoimmune encephalomyelitis (EAE) model of MS we revealed specific changes in the mRNA and protein expression of key molecules involved in the maintaining of cholesterol homeostasis in the rat spinal cord: 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR), apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46A1) during the course of disease. The presence of myelin lipid debris was seen only at the peak of EAE in demyelination loci being efficiently removed during the recovery period. Since CYP46A1 is responsible for removal of cholesterol excess, we performed a detailed profiling of CYP46A1 expression and revealed regional and temporal specificities in its distribution. Double immunofluorescence staining demonstrated CYP46A1 localization with neurons, infiltrated macrophages, microglia and astrocytes in the areas of demyelination, suggesting that these cells play a role in cholesterol turnover in EAE. We propose that alterations in the regulation of cholesterol metabolism at the onset and peak of EAE may add to the progression of disease, while during the recovery period may have beneficial effects contributing to the regeneration of myelin sheath and restoration of neuronal function.

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Oxysterols regulate encephalitogenic CD4+ T cell trafficking during central nervous system autoimmunity

Cited by 81 publications

References 36 publications

Interdependence of oxysterols with cholesterol profiles in multiple sclerosis

Interdependence of oxysterols with cholesterol profiles in multiple sclerosis

Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord

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