Membrane-Bound Metallothionein 1 of Murine Dendritic Cells Promotes the Expansion of Regulatory T Cells In Vitro

Spiering, Rachel; Wagenaar-Hilbers, Josée P A; Huijgen, Veerle; Zee, Ruurd van der; Kooten, Peter J. S. van; Eden, Willem van; Broere, Femke

doi:10.1093/toxsci/kft268

Cited by 19 publications

(20 citation statements)

References 46 publications

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“…It is clear that DCs that have been treated with carvacrol plus thermal stress produce high levels of MT-1 mRNA and have the phenotype of tolerogenic cells that suppress arthritis [50]. Furthermore, the membrane-bound MT-1 of tolerogenic DCs induced a FoxP3 + phenotype in antigen-specific CD4 + T cells and promoted the expansion of these regulatory T cells [35]. Thus, these data suggested that MT-1 could induce the production of regulatory T cells from CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Metallothionein‐1 suppresses rheumatoid arthritis pathogenesis by shifting the Th17/Treg balance

Sun

et al. 2018

Eur J Immunol

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It is now well accepted that an imbalance between the Th17 and regulatory T-cell responses is closely associated with the development of rheumatoid arthritis (RA). However, the precise regulatory mechanism for the differentiation of Th17 and Treg in RA is not well characterized. The present study showed that metallothionein-1 (MT-1), which is a low molecular weight protein that is involved in the detoxification of heavy metals and scavenging of free radicals, was upregulated in RA. Furthermore, the synovial inflammation and pathologic symptoms in collagen-induced arthritis and collagen antibody-induced arthritis mice were significantly suppressed when MT-1 was expressed intraarticularly. Further investigation revealed that MT-1 inhibited the differentiation of Th17 cells but enhanced that of Treg cells. Furthermore, it markedly decreased both STAT3 and RAR-related orphan receptor gamma t (RORγt) expression in vitro and in vivo. Collectively, our studies demonstrated that MT-1 might manifest as a protein involved in immunosuppression of RA pathogenesis by shifting Th17/Treg balance and may prove to be a potential therapeutic target for RA autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Metallothionein‐1 suppresses rheumatoid arthritis pathogenesis by shifting the Th17/Treg balance

Sun

et al. 2018

Eur J Immunol

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“…These are small cysteine-rich metal-binding proteins involved in the regulation of homeostasis of zinc and other heavy metals at cytoplasmic level ( 37 ). MTs can also affect different cellular processes such as gene expression, apoptosis, proliferation, and differentiation ( 38 ) and have been described to suppress collagen-induced arthritis via induction of TGF-β and reduction of pro-inflammatory modulators such as TNF ( 39 ) and to promote the expansion of Treg ( 40 , 41 ). Besides MTs, another molecule involved in zinc transport, the zinc importer SLC39A8/ZIP8, is also highly upregulated in DM-DCs.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone and Monophosphoryl Lipid A Induce a Distinctive Profile on Monocyte-Derived Dendritic Cells through Transcriptional Modulation of Genes Associated With Essential Processes of the Immune Response

et al. 2017

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There is growing interest in the use of tolerogenic dendritic cells (tolDCs) as a potential target for immunotherapy. However, the molecular bases that drive the differentiation of monocyte-derived DCs (moDCs) toward a tolerogenic state are still poorly understood. Here, we studied the transcriptional profile of moDCs from healthy subjects, modulated with dexamethasone (Dex) and activated with monophosphoryl lipid A (MPLA), referred to as Dex-modulated and MPLA-activated DCs (DM-DCs), as an approach to identify molecular regulators and pathways associated with the induction of tolerogenic properties in tolDCs. We found that DM-DCs exhibit a distinctive transcriptional profile compared to untreated (DCs) and MPLA-matured DCs. Differentially expressed genes downregulated by DM included MMP12, CD1c, IL-1B, and FCER1A involved in DC maturation/inflammation and genes upregulated by DM included JAG1, MERTK, IL-10, and IDO1 involved in tolerance. Genes related to chemotactic responses, cell-to-cell signaling and interaction, fatty acid oxidation, metal homeostasis, and free radical scavenging were strongly enriched, predicting the activation of alternative metabolic processes than those driven by counterpart DCs. Furthermore, we identified a set of genes that were regulated exclusively by the combined action of Dex and MPLA, which are mainly involved in the control of zinc homeostasis and reactive oxygen species production. These data further support the important role of metabolic processes on the control of the DC-driven regulatory immune response. Thus, Dex and MPLA treatments modify gene expression in moDCs by inducing a particular transcriptional profile characterized by the activation of tolerance-associated genes and suppression of the expression of inflammatory genes, conferring the potential to exert regulatory functions and immune response modulation.

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“…Mounting evidence suggests that DCs modulate MTs in response to molecular cues, and that they may, in fact, regulate their phenotype and function. LPS upregulates MT2A in mature and activated human DCs [ 111 ], but downregulates MT1 in mouse bone marrow derived DCs [ 112 ]. Murine DCs express MT1 in response to thermal stress, dexamethasone or ZnCl 2 [ 112 , 113 ].…”

Section: Metallothionein Induction and Signaling In Immunitymentioning

confidence: 99%

Metallothioneins: Emerging Modulators in Immunity and Infection

Vignesh

Deepe

2017

IJMS

178

116

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Metallothioneins (MTs) are a family of metal-binding proteins virtually expressed in all organisms including prokaryotes, lower eukaryotes, invertebrates and mammals. These proteins regulate homeostasis of zinc (Zn) and copper (Cu), mitigate heavy metal poisoning, and alleviate superoxide stress. In recent years, MTs have emerged as an important, yet largely underappreciated, component of the immune system. Innate and adaptive immune cells regulate MTs in response to stress stimuli, cytokine signals and microbial challenge. Modulation of MTs in these cells in turn regulates metal ion release, transport and distribution, cellular redox status, enzyme function and cell signaling. While it is well established that the host strictly regulates availability of metal ions during microbial pathogenesis, we are only recently beginning to unravel the interplay between metal-regulatory pathways and immunological defenses. In this perspective, investigation of mechanisms that leverage the potential of MTs to orchestrate inflammatory responses and antimicrobial defenses has gained momentum. The purpose of this review, therefore, is to illumine the role of MTs in immune regulation. We discuss the mechanisms of MT induction and signaling in immune cells and explore the therapeutic potential of the MT-Zn axis in bolstering immune defenses against pathogens.

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Membrane-Bound Metallothionein 1 of Murine Dendritic Cells Promotes the Expansion of Regulatory T Cells In Vitro

Cited by 19 publications

References 46 publications

Metallothionein‐1 suppresses rheumatoid arthritis pathogenesis by shifting the Th17/Treg balance

Metallothionein‐1 suppresses rheumatoid arthritis pathogenesis by shifting the Th17/Treg balance

Dexamethasone and Monophosphoryl Lipid A Induce a Distinctive Profile on Monocyte-Derived Dendritic Cells through Transcriptional Modulation of Genes Associated With Essential Processes of the Immune Response

Metallothioneins: Emerging Modulators in Immunity and Infection

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