Human natural Treg microRNA signature: Role of microRNA‐31 and microRNA‐21 in FOXP3 expression

Rouas, Rédouane; Fawad-Kazan, Hussein; Zein, Nabil El; Lewalle, Philippe; Rothé, Françoise; Simion, Alexandru; Akl, Haidar; Mourtada, Mohamad; Rifai, Mohamad El; Burny, Arsène; Romero, Pedro; Martiat, Philippe; Badran, Bassam

doi:10.1002/eji.200838509

Cited by 257 publications

(254 citation statements)

References 30 publications

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“…miR-21 was found to be highly represented in effector and memory T cells compared with naive CD8 + T cells (50). In human Tregs, miR-21 was found to act as a positive, although indirect, regulator of FOXP3 expression (51). Furthermore, miR-21 was found to be overexpressed in CD4 + T cells derived both from patients with lupus and from lupus-prone MRL/lpr mice (52).…”

Section: Discussionmentioning

confidence: 99%

microRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination

Mycko

Cichalewska²,

Machlańska³

et al. 2012

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

179

143

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MicroRNAs (miRNAs) are an emerging group of short, noncoding RNAs that play an important role in regulating expression of classical genes. Thus far little is known about their role in autoimmune demyelination. In this study, we analyzed changes in the miRNA profile in CD4 + T cells that occurred during the recognition of the myelin autoantigen, MOG . We found that, both in vivo and in vitro, myelin antigen stimulation resulted in significant up-regulation of miR-301a, miR-21, and miR-155. Furthermore, these three miRNAs were overexpressed in T cells infiltrating the CNS in animals with experimental autoimmune encephalomyelitis. Use of specific miRNA antagonists, antagomirs, revealed that miR-301a contributed to the development of the T-helper type 17 subset via targeting the IL-6/23-STAT3 pathway. This contribution appeared to be mediated by the miR-301a effect on the expression of the PIAS3, a potent inhibitor of the STAT3 pathway. Manipulation of miR-301a levels or PIAS3 expression in myelin-specific CD4 + T cells led to significant changes in the severity of experimental autoimmune encephalomyelitis. Thus, we have identified a role of miR-301a in regulating the function of myelinreactive T-helper type 17 cells, supporting a role for miR-301a and PIAS3 as candidates for therapeutic targets for controlling of autoimmune demyelination.M ultiple sclerosis (MS) is an organ-specific autoimmune disease manifested by chronic inflammatory demyelination of the CNS. CD4 + T-cell-mediated autoimmunity, with a critical role of a putative myelin autoantigen, has long been accepted as one of the most important aspects of MS pathogenesis, especially for the early initiation of disease (1). This understanding has been particularly complemented by the research on the MS animal model, experimental autoimmune encephalomyelitis (EAE). T-helper type 1 (Th1) cells, characterized by the expression of the transcription factor T-bet and the production of IFN-γ, originally were considered the major effector T-helper cells that mediate the pathogenesis of autoimmune demyelination (2). More recently another subset of T-helper cells, Th17, characterized by expression of the transcription factors retinoic acid receptor-related orphan receptor alpha (ROR-α) and retinoic acid receptor-related orphan receptor gamma t (ROR-γt) and by the production of IL-17, has been considered pivotal for the propagation of autoimmune demyelination (3). Mice with impaired numbers or function of Th17 cells, particularly mice deficient in the cytokines IL-6 or IL-23, are largely resistant to EAE (4-6). However, precise mechanisms governing the development and function of Th17 cells resulting in autoimmune demyelination are still unclear. Thus, Th17-targeting therapeutic approaches for MS have not yet been established.MicroRNAs (miRNAs) have begun to emerge as an important component in the differentiation and function of cells involved in the immune response. miRNAs operate as noncoding RNA molecules ∼22 nt in length that are processed from larger transcripts o...

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Section: Discussionmentioning

confidence: 99%

microRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination

Mycko

Cichalewska²,

Machlańska³

et al. 2012

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

179

143

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“…The modifiable mediators of this regulation include methylation,37, 38, 39, 40, 41, 42, 43, 44 acetylation45, 46, 47 and microRNA‐mediated control of transcript translation 28, 48, 49, 50, 51, 52, 53, 54, 55. The global regulation of FOXP3 is influenced by chromatin organises, including SATB1 acts both during development and in mature cells 48, 58.…”

Section: Foxp3 Epigenetic Regulationmentioning

confidence: 99%

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

et al. 2018

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Regulatory T cells (Treg) are critical for preventing autoimmunity and curtailing responses of conventional effector T cells (Tconv). The reprogramming of T‐cell fate and function to generate Treg requires switching on and off of key gene regulatory networks, which may be initiated by a subtle shift in expression levels of specific genes. This can be achieved by intermediary regulatory processes that include microRNA and long noncoding RNA‐based regulation of gene expression. There are well‐documented microRNA profiles in Treg and Tconv, and these can operate to either reinforce or reduce expression of a specific set of target genes, including FOXP3 itself. This type of feedforward/feedback regulatory loop is normally stable in the steady state, but can alter in response to local cues or genetic risk. This may go some way to explaining T‐cell plasticity. In addition, in chronic inflammation or autoimmunity, altered Treg/Tconv function may be influenced by changes in enhancer–promoter interactions, which are highly cell type‐specific. These interactions are impacted by genetic risk based on genome‐wide association studies and may cause subtle alterations to the gene regulatory networks controlled by or controlling FOXP3 and its target genes. Recent insights into the 3D organisation of chromatin and the mapping of noncoding regulatory regions to the genes they control are shedding new light on the direct impact of genetic risk on T‐cell function and susceptibility to inflammatory and autoimmune conditions.

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“…57 In addition, miR-21 and miR-31 regulate Treg development by changing Foxp3 expression. 58 Several miRNAs have been reported to promote Th17 cell development. For example, miR-326 facilitates Th17 development and accelerates the progression of autoimmunity by directly inhibiting ETS1, which is a negative modulator of Th17 differentiation.…”

Section: Mirnas: Regulators Of Immune Pathogenesis In T1dmentioning

confidence: 99%

“…68 miR-31 has been demonstrated to reduce Foxp3 expression. 58 Similar to miR-101, miR-26a has also been shown to target Ezh2, which is related to Foxp3 expression and the suppressive functions of nTregs. 68 Jeker et al found that miR-10a expression was lower in Tregs from NOD mice than in Tregs from autoimmunity-resistant C57BL/ 6 mice.…”

Section: Mirnas: Regulators Of Immune Pathogenesis In T1dmentioning

confidence: 99%

miRNAs: novel regulators of autoimmunity-mediated pancreatic β-cell destruction in type 1 diabetes

2017

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MicroRNAs (miRNAs) are a series of conserved, short, non-coding RNAs that modulate gene expression in a posttranscriptional manner. miRNAs are involved in almost every physiological and pathological process. Type 1 diabetes (T1D) is an autoimmune disease that is the result of selective destruction of pancreatic β-cells driven by the immune system. miRNAs are also important participants in T1D pathogenesis. Herein, we review the most recent data on the potential involvement of miRNAs in T1D. Specifically, we focus on two aspects: the roles of miRNAs in maintaining immune homeostasis and regulating β-cell survival and/or functions in T1D. We also discuss circulating miRNAs as potent biomarkers for the diagnosis and prediction of T1D and investigate potential therapeutic approaches for this disease.

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Human natural Treg microRNA signature: Role of microRNA‐31 and microRNA‐21 in FOXP3 expression

Cited by 257 publications

References 30 publications

microRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination

microRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

miRNAs: novel regulators of autoimmunity-mediated pancreatic β-cell destruction in type 1 diabetes

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