A Single miRNA-mRNA Interaction Affects the Immune Response in a Context- and Cell-Type-Specific Manner

Lu, Li-Fan; Gasteiger, Georg; Yu, I-Shing; Chaudhry, Ashutosh; Hsin, Jing-Ping; Lu, Yuheng; Bos, Paula D.; Lin, Ling-Li; Zawislak, Carolyn L.; Cho, Sunglim; Sun, Joseph C.; Leslie, Christina; Lin, Shu‐Wha; Rudensky, Alexander Y.

doi:10.1016/j.immuni.2015.04.022

Cited by 156 publications

(162 citation statements)

References 39 publications

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“…Interestingly miR-155 is involved in the expansion of virus-specific NK cells, the latter being mediated through specific inhibition of SOCS1. 27 Taken together, these annotation analyses confirm the importance of the differentially methylated loci identified in our study as playing an important role in NK cell activation.…”

Section: ¡3supporting

confidence: 84%

The DNA methylation profile of activated human natural killer cells

et al. 2016

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Natural killer (NK) cells are now recognized to exhibit characteristics akin to cells of the adaptive immune system. The generation of adaptive memory is linked to epigenetic reprogramming including alterations in DNA methylation. The study herein found reproducible genome wide DNA methylation changes associated with human NK cell activation. Activation led predominately to CpG hypomethylation (81% of significant loci). Bioinformatics analysis confirmed that non-coding and gene-associated differentially methylated sites (DMS) are enriched for immune related functions (i.e., immune cell activation). Known DNA methylation-regulated immune loci were also identified in activated NK cells (e.g., TNFA, LTA, IL13, CSF2). Twenty-one loci were designated high priority and further investigated as potential markers of NK activation. BHLHE40 was identified as a viable candidate for which a droplet digital PCR assay for demethylation was developed. The assay revealed high demethylation in activated NK cells and low demethylation in na€ ıve NK, T-and B-cells. We conclude the NK cell methylome is plastic with potential for remodeling. The differentially methylated region signature of activated NKs revealed similarities with T cell activation, but also provided unique biomarker candidates of NK activation, which could be useful in epigenome-wide association studies to interrogate the role of NK subtypes in global methylation changes associated with exposures and/or disease states.

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Section: ¡3supporting

confidence: 84%

The DNA methylation profile of activated human natural killer cells

et al. 2016

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“…This finding has important clinical implications given mir‐155 expression is increased in active MS lesions. Additionally, the validated miR‐155 target SOCS138 is a potent regulator of astrocyte cytokine/chemokine secretion,39 suggesting that a miR‐155/SOCS1 axis could mediate the anti‐inflammatory effects of DMF. miR‐146a is an inflammation resolving microRNA whose expression is upregulated in CNS lesions and peripheral immune cells of MS patients 35, 36.…”

Section: Discussionmentioning

confidence: 99%

Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation

Galloway

Williams

Moore

2017

Ann Clin Transl Neurol

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ObjectiveDimethyl fumarate (DMF) is a fumaric acid ester approved for the treatment of relapsing‐remitting multiple sclerosis (RRMS). In both the brain and periphery, DMF and its metabolite monomethyl fumarate (MMF) exert anti‐inflammatory and antioxidant effects. Our aim was to compare the effects of DMF and MMF on inflammatory and antioxidant pathways within astrocytes, a critical supporting glial cell in the central nervous system (CNS). Direct effects of fumarates on neural progenitor cell (NPC) differentiation toward the oligodendrocyte lineage were also assessed.MethodsPrimary astrocyte cultures were derived from both murine and human brains. Following pretreatment with MMF, DMF, or vehicle, astrocytes were stimulated with IL‐1β for 24 h; gene and microRNA expression were measured by qPCR. Cytokine production and reactive oxygen species (ROS) generation were also measured. NPCs were differentiated into the oligodendrocyte lineage in the presence of fumarates and immunostained using early oligodendrocyte markers.ResultsIn both murine and human astrocytes, DMF, but not MMF, significantly reduced secretion of IL‐6, CXCL10, and CCL2; neither fumarate promoted a robust increase in antioxidant gene expression, although both MMF and DMF prevented intracellular ROS production. Pretreatment with fumarates reduced microRNAs ‐146a and ‐155 upon stimulation. In NPC cultures, DMF increased the number of O4+ and NG2+ cells.InterpretationThese results suggest that DMF, and to a lesser extent MMF, mediates the anti‐inflammatory effects within astrocytes. This is supported by recent observations that in the inflamed CNS, DMF may be the active compound mediating the anti‐inflammatory effects independent from altered antioxidant gene expression.

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“…Although early reports of large-scale dedifferentiation of Treg cells into Th1/17 effectors were likely artifacts of incompletely tight lineage-tracing systems or of transfer into alymphoid hosts, exposure of Treg cells to conditions of inflammatory stress or deficiency in trophic cytokines destabilizes FoxP3 expression, removing its repression of cytokine and other effector genes. This stability is reinforced at the molecular level by specific demethylation at particular regions of the Foxp3 locus and other key Treg transcripts that correlate with stable expression and by feedback loops involving protein cofactors and miRNAs that act as genetic switches to lock in the core Treg phenotype (30,31).…”

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confidence: 99%

Unstable FoxP3 ⁺ T regulatory cells in NZW mice

Dépis

Kwon

Mathis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Regulatory T (Treg) cells that express the transcription factor FoxP3 play a key role in self-tolerance and the control of inflammation. In mice and humans, there is a wide interindividual range in Treg frequency, but little is known about the underlying genetic or epigenetic mechanisms. We explored this issue in inbred strains of mice, with a special focus on the low proportion of Treg cells found in NZW mice. Mixed bone marrow chimera experiments showed this paucity to be intrinsic to NZW Treg cells, a dearth that could be tied to poor stability of the Treg pool and of FoxP3 expression. This instability was not a consequence of differential epigenetic marks, because Treg-specific CpG hypomethylation profiles at the Foxp3 locus were similar in all strains tested. It was also unrelated to the high expression of IFN signature genes in NZW, as shown by intercross to mice with an Ifnar1 knockout. NZW Tregs were less sensitive to limiting doses of trophic cytokines, IL-2 and -33, for population homeostasis and for maintenance of FoxP3 expression. Gene-expression profiles highlighted specific differences in the transcriptome of NZW Tregs compared with those of other strains, but no single defect could obviously account for the instability. Rather, NZW Tregs showed a general up-regulation of transcripts normally repressed in Treg cells, and we speculate that this network-level bias may account for NZW Treg instability.Treg homeostasis | FoxP3 stability | immunoregulation | inbred mice

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A Single miRNA-mRNA Interaction Affects the Immune Response in a Context- and Cell-Type-Specific Manner

Cited by 156 publications

References 39 publications

The DNA methylation profile of activated human natural killer cells

The DNA methylation profile of activated human natural killer cells

Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation

Unstable FoxP3 ⁺ T regulatory cells in NZW mice

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A Single miRNA-mRNA Interaction Affects the Immune Response in a Context- and Cell-Type-Specific Manner

Cited by 156 publications

References 39 publications

The DNA methylation profile of activated human natural killer cells

The DNA methylation profile of activated human natural killer cells

Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation

Unstable FoxP3 + T regulatory cells in NZW mice

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Unstable FoxP3 ⁺ T regulatory cells in NZW mice