Dicer-Dependent MicroRNA Pathway Controls Invariant NKT Cell Development

Fedeli, Maya; Napolitano, Anna; Wong, Molly Pui Man; Marçais, Antoine; Lalla, Claudia de; Colucci, Francesco; Merkenschlager, Matthias; Dellabona, Paolo

doi:10.4049/jimmunol.0901361

Cited by 85 publications

(97 citation statements)

References 37 publications

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“…This phenomenon has been linked in particular to the loss of function of miRNA-deficient Tregs, and mice with either a general deficiency of miRNA or selective knockdown of miR-146a in Tregs displayed a fatal autoimmune disease (26)(27)(28)(29)(30). However, miRNA ablation in T cells also results in defects in natural killer T-cell development (31,32) and the differentiation of T-helper cells that may contribute independently to autoimmunity (25,33).…”

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

View full text Add to dashboard Cite

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“…One possible reason is that in their transferring experiments, four to five mice per group may not have enough power to detect a difference for this mild reduction, compared with the almost complete blocking of early iNKT cell development in the mice with miR-150 overexpression. Compared with iNKT cells in bone marrow-or thymus-specific total miRNA deletion mouse models (26)(27)(28), miR-150 deletion alone is unlikely accountable for the profound interruption of iNKT cell development, maturation, and function identified in those mice. This may suggest the potential involvement of multiple miRNAs or groups of miRNAs in iNKT cell developmental and functional regulation, which is also supported by our recent miRNA expression profiles of iNKT cells (Q.H.…”

Section: Discussionmentioning

confidence: 99%

“…Small microRNAs (miRNAs) are short noncoding RNAs (20-23 nt) that negatively regulate gene expression by inducing the degradation or translational repression of the target protein-coding mRNAs (25). Recently, our laboratory and another group found that deletion of Dicer, the RNase III enzyme essential for the processing of mature functional miRNAs, results in a profound interruption of iNKT cell development, maturation, and function (26)(27)(28). However, little insight has been made concerning the role of specific miRNAs in the development and function of iNKT cells.…”

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confidence: 99%

MicroRNA miR-150 Is Involved in Vα14 Invariant NKT Cell Development and Function

Zheng

Zhou

2012

The Journal of Immunology

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CD1d-restricted Vα14 invariant NKT (iNKT) cells play an important role in the regulation of diverse immune responses. MicroRNA-mediated RNA interference is emerging as a crucial regulatory mechanism in the control of iNKT cell differentiation and function. Yet, roles of specific microRNAs in the development and function of iNKT cells remain to be further addressed. In this study, we identified the gradually increased expression of microRNA-150 (miR-150) during the maturation of iNKT cells in thymus. Using miR-150 knockout (KO) mice, we found that miR-150 deletion resulted in an interruption of iNKT cell final maturation in both thymus and periphery. Upon activation, iNKT cells from miR-150KO mice showed significantly increased IFN-γ production compared with wild-type iNKT cells. Bone marrow-transferring experiments demonstrated the cell-intrinsic characteristics of iNKT cell maturation and functional defects in mice lacking miR-150. Furthermore, miR-150 target c-Myb was significantly upregulated in miR-150KO iNKT cells, which potentially contribute to iNKT cell defects in miR-150KO mice. Our data define a specific role of miR-150 in the development and function of iNKT cells.

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“…A Dicer dependent miRNA pathway is important in the regulation of invariant NK T cell differentiation, func tion, and homeostasis [53] . The normal granulocytic differentiation requires the zinc finger protein growth factor independent1, which is a transcription inhibitor that regulates the expression of miR21 and miR 196b during myelopoiesis [54] .…”

Section: Mirnas and Other Kind Of Innate Immune Cellsmentioning

confidence: 99%

miRNAs as new molecular insights into inflammatory bowel disease: Crucial regulators in autoimmunity and inflammation

Zhang

2016

WJG

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Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammatory disorders of the gastrointestinal tract, and includes two major phenotypes: ulcerative colitis and Crohn's disease. The pathogenesis of IBD is not fully understood as of yet. It is believed that IBD results from complicated interactions between environmental factors, genetic predisposition, and immune disorders. miRNAs are a class of small non-coding RNAs that can regulate gene expression by targeting the 3′-untranslated region of specific mRNAs for degradation or translational inhibition. miRNAs are considered to play crucial regulatory roles in many biologic processes, such as immune cellular differentiation, proliferation, and apoptosis, and maintenance of immune homeostasis. Recently, aberrant expression of miRNAs was revealed to play an important role in autoimmune diseases, including IBD. In this review, we discuss the current understanding of how miRNAs regulate autoimmunity and inflammation by affecting the differentiation, maturation, and function of various immune cells. In particular, we focus on describing specific miRNA expression profiles in tissues and peripheral blood that may be associated with the pathogenesis of IBD. In addition, we summarize the opportunities for utilizing miRNAs as new biomarkers and as potential therapeutic targets in IBD.

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Dicer-Dependent MicroRNA Pathway Controls Invariant NKT Cell Development

Cited by 85 publications

References 37 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

MicroRNA miR-150 Is Involved in Vα14 Invariant NKT Cell Development and Function

miRNAs as new molecular insights into inflammatory bowel disease: Crucial regulators in autoimmunity and inflammation

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