Corticosteroid receptor expression and in vivo glucocorticoid sensitivity in multiple sclerosis

Bechmann, Lukas; Busse, Kathy; Stoppe, Muriel; Cotte, Steffi; Ettrich, Barbara; Bergh, Florian Then

doi:10.1016/j.jneuroim.2014.07.004

Cited by 11 publications

(10 citation statements)

References 36 publications

(38 reference statements)

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“…Although the precise demethylation mechanism remains unknown, data of Wiench et al 50 suggest that active demethylation takes place. Compared to the IFN analysis, we did not observe a very strong GC signature in the EPIC array data nor in the WGBS data, since in other common GC-regulated genes, such as FKBP5, TSC22D3 and DUSP1 47,51,52 , no DNA methylation differences were observed. Altogether, our data reveals the ZBTB16 DMP (cg25345365) as an epigenetic biomarker for GC treatment, and future studies have to assess its utility to predict clinical GC response in patients with inflammatory or autoimmune diseases receiving GC therapy.…”

Section: Discussioncontrasting

confidence: 74%

DNA Methylation Signatures of a Large Cohort Monozygotic Twins Clinically Discordant for Multiple Sclerosis

Souren

Gerdes

Lutsik

et al. 2018

Preprint

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system with a modest concordance rate in monozygotic twins that strongly argues for involvement of epigenetic factors. We observe in 45 MS discordant monozygotic twins highly similar peripheral blood mononuclear cell-based methylomes. However, a few MS-associated differentially methylated positions (DMP) were identified and validated, including a region in the TMEM232 promoter and ZBTB16 enhancer. In CD4+ T cells we observed an MS-associated differentially methylated region in FIRRE. In addition, many regions showed large methylation differences in individual pairs, but were not clearly associated with MS. Furthermore, epigenetic biomarkers for current interferon-beta treatment were identified, and extensive validation revealed the ZBTB16 DMP as a signature of prior glucocorticoid treatment. Altogether, our study represents an important reference for epigenomic MS studies. It identifies new candidate epigenetic markers, highlights treatment effects and genetic background as major confounders, and argues against some previously reported MS-associated epigenetic candidates.

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Section: Discussioncontrasting

confidence: 74%

DNA Methylation Signatures of a Large Cohort Monozygotic Twins Clinically Discordant for Multiple Sclerosis

Souren

Gerdes

Lutsik

et al. 2018

Preprint

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“…In one study, application of the MR agonist deoxycorticosterone acetate was found to aggravate EAE, which could be prevented using the MR antagonist spironolactone ( 17 ). Furthermore, a reduction of MR expression in whole blood cells was found in MS patients ( 18 ). While these findings indicate a potential involvement of the MR in modulating neuroinflammatory diseases, there have been very few studies addressing this topic overall.…”

Section: Introductionmentioning

confidence: 99%

Deletion of the Mineralocorticoid Receptor in Myeloid Cells Attenuates Central Nervous System Autoimmunity

Montes-Cobos¹,

Schweingruber²,

Li³

et al. 2017

Front. Immunol.

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Myeloid cells play an important role in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Monocytes, macrophages, and microglia can adopt two distinct phenotypes, with M1-polarized cells being more related to inflammation and autoimmunity while M2-polarized cells contribute to tissue repair and anti-inflammatory processes. Here, we show that deletion of the mineralocorticoid receptor (MR) in bone marrow-derived macrophages and peritoneal macrophages caused their polarization toward the M2 phenotype with its distinct gene expression, altered phagocytic and migratory properties, and dampened NO production. After induction of EAE, mice that are selectively devoid of the MR in their myeloid cells (MRlysM mice) showed diminished clinical symptoms and ameliorated histological hallmarks of neuroinflammation. T cells in peripheral lymphoid organs of these mice produced less pro-inflammatory cytokines while their proliferation and the abundance of regulatory T cells were unaltered. The numbers of inflammatory monocytes and reactive microglia in the central nervous system (CNS) in MRlysM mice were significantly lower and they adopted an M2-polarized phenotype based on their gene expression profile, presumably explaining the ameliorated neuroinflammation. Our results indicate that the MR in myeloid cells plays a critical role for CNS autoimmunity, providing a rational to interfere with diseases such as MS by pharmacologically targeting this receptor.

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“…They found GILZ to be significantly up-regulated in patients with mild or moderate disability compared to controls, while patients with severe disability showed GILZ concentrations to be lower than in healthy controls, suggesting the contribution of these genes in disease pathogenesis. They hypothesized that at the initial MS stages, HPA hyperactivity results in high cortisol levels, which in turn induce the expression of GR target genes, aiming to control neuroinflammation 12 .…”

Section: Discussionmentioning

confidence: 99%

“…The association of GC resistance with the inflammatory disease activity 11 indicates that modification of GC resistance might be a target for novel therapeutic strategies. Moreover, the assessment of the in vivo glucocorticoid sensitivity in MS using the expression of GR-target genes (GILZ, DUSP, FKBP) has revealed up-regulation of GR targeted genes in patients with mild to moderate disability, while patients with severe disability displayed gene transcription concentration lower than healthy controls 12 , supporting further GC resistance in MS patients.…”

Section: Introductionmentioning

confidence: 98%

Methylprednisolone stimulated gene expression (GILZ, MCL-1) and basal cortisol levels in multiple sclerosis patients in relapse are associated with clinical response

Evangelopoulos

Nasiri-Ansari

Kassi

et al. 2021

Sci Rep

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Glucocorticoids (GCs) are the main treatment of relapse in multiple sclerosis (MS). Decreased sensitivity to GCs in MS patients has been associated with lack of the suppressive effect of GCs on inflammatory molecules as well as increased resistance to apoptosis. We investigated GC-sensitivity by measuring the effect of intravenous methylprednisolone (IVMP) treatment on transactivation of anti-inflammatory and apoptotic genes (GILZ, MCL-1 and NOXA respectively), in accordance to clinical outcome. Thirty nine MS patients were studied: 15 with clinically isolated syndrome (CIS), 12 with relapsing remitting (RRMS) and 12 with secondary progressive (SPMS) under relapse. Patients underwent treatment with IVMP for 5 days. Blood was drawn before IVMP treatment on day 1 and 1 h after IVMP treatment on days 1 and 5. GIlZ, MCL-1 and NOXA were determined by qPCR. The Expanded Disability Status was evaluated and patients were divided according to their clinical response to IVMP. GILZ and MCL-1 gene expression were significantly higher following first IVMP treatment in responders, compared to non-responders. Furthermore, serum basal cortisol and 1,25-OH Vitamin D levels were significantly higher in clinical-responders as compared to non-clinical responders. Our findings suggest that the differential GILZ and MCL-1 gene expression between clinical-responders and non-clinical responders may implicate the importance of GILZ and MCL-1 as possible markers for predicting glucocorticoid sensitivity and response to GC-therapy in MS patients following first IVMP injection.

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Corticosteroid receptor expression and in vivo glucocorticoid sensitivity in multiple sclerosis

Cited by 11 publications

References 36 publications

DNA Methylation Signatures of a Large Cohort Monozygotic Twins Clinically Discordant for Multiple Sclerosis

DNA Methylation Signatures of a Large Cohort Monozygotic Twins Clinically Discordant for Multiple Sclerosis

Deletion of the Mineralocorticoid Receptor in Myeloid Cells Attenuates Central Nervous System Autoimmunity

Methylprednisolone stimulated gene expression (GILZ, MCL-1) and basal cortisol levels in multiple sclerosis patients in relapse are associated with clinical response

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