MiR-125a targets effector programs to stabilize Treg-mediated immune homeostasis

Pan, Wen; Zhu, Shu; Dai, Dai; Liu, Zheng; Li, Dan; Li, Bin; Gagliani, Nicola; Zheng, Yunjiang; Tang, Yue; Weirauch, Matthew T.; Rothenberg, Marc E.; Zhu, Wenjun; Wang, Yue; Chen, Bin; Qian, Youcun; Chen, Yingxuan; Fang, Jing‐Yuan; Herbst, Ronald; Richman, Laura K.; Jallal, Bahija; Harley, John B.; Flavell, Richard A.; Yao, Yihong; Shen, Nan

doi:10.1038/ncomms8096

Cited by 119 publications

(96 citation statements)

References 49 publications

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“…Some of the up-regulated miRNAs have well-documented roles that support this hypothesis. Notably, miR-125a suppresses several effector T-cell factors such as Stat3 and Ifng and stabilizes the commitment and immunomodulatory capacity of Tregs during EAE (54). Moreover, most of the up-regulated miRNAs analyzed here were also hypomethylated, which suggests that VDR/RXR binding may directly activate miRNAs, and they in turn mediate down-regulation of proteincoding genes.…”

Section: Discussionmentioning

confidence: 82%

Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

Zeitelhofer

Adzemovic

Gomez-Cabrero

et al. 2017

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

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Vitamin D exerts multiple immunomodulatory functions and has been implicated in the etiology and treatment of several autoimmune diseases, including multiple sclerosis (MS). We have previously reported that in juvenile/adolescent rats, vitamin D supplementation protects from experimental autoimmune encephalomyelitis (EAE), a model of MS. Here we demonstrate that this protective effect associates with decreased proliferation of CD4+ T cells and lower frequency of pathogenic T helper (Th) 17 cells. Using transcriptome, methylome, and pathway analyses in CD4+ T cells, we show that vitamin D affects multiple signaling and metabolic pathways critical for T-cell activation and differentiation into Th1 and Th17 subsets in vivo. Namely, Jak/Stat, Erk/Mapk, and Pi3K/Akt/mTor signaling pathway genes were down-regulated upon vitamin D supplementation. The protective effect associated with epigenetic mechanisms, such as (i) changed levels of enzymes involved in establishment and maintenance of epigenetic marks, i.e., DNA methylation and histone modifications; (ii) genome-wide reduction of DNA methylation, and (iii) up-regulation of noncoding RNAs, including microRNAs, with concomitant down-regulation of their protein-coding target RNAs involved in T-cell activation and differentiation. We further demonstrate that treatment of myelin-specific T cells with vitamin D reduces frequency of Th1 and Th17 cells, down-regulates genes in key signaling pathways and epigenetic machinery, and impairs their ability to transfer EAE. Finally, orthologs of nearly 50% of candidate MS risk genes and 40% of signature genes of myelin-reactive T cells in MS changed their expression in vivo in EAE upon supplementation, supporting the hypothesis that vitamin D may modulate risk for developing MS. Vitamin D deficiency is one of the most consistently reported environmental factor in the etiology of multiple sclerosis (MS) (5), a chronic inflammatory disease of the CNS characterized by autoimmune destruction of myelin, axonal loss, and brain atrophy (6). Increased risk of developing MS has been described in carriers of rare and common variants of the CYP27B gene (7, 8), which encodes the enzyme that catalyzes the last step in converting vitamin D to its active form, from 25(OH)D 3 to 1,25 (OH) 2 D 3 . These studies imply a causal role of low vitamin D in MS, which has recently been further supported by Mendelian randomization studies in two large cohorts demonstrating that three genetic variants that associate with serum 25(OH)D 3 levels also associate with the risk of developing MS (9). However, high levels of vitamin D have been associated not only with the reduced risk of developing MS (10, 11) but also with the reduced risk for relapses, new brain lesions, and subsequent disability (12, 13). Moreover, it has been described that increased levels of vitamin D can reduce serum levels of . Most of what is known about the immunological mechanisms of vitamin D in MS comes from the studies in its animal model, experimental autoimmune encephalomyelitis (...

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Section: Discussionmentioning

confidence: 82%

Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

Zeitelhofer

Adzemovic

Gomez-Cabrero

et al. 2017

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

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“…30). We performed 5 0 -RACE to determine the transcription starting site of Spaca6/pri-miR-125a using cDNA generated from BMDMs ( Supplementary Fig.…”

Section: Identification Of Mir-125a As a Downstream Molecule Of Notchmentioning

confidence: 99%

“…miR-125a is enriched in myeloid progenitors but at low level in monocytes (25,26), and is upregulated in M1 and downregulated in M2 macrophages (23,24). miR-125a is involved in differential activation of macrophages and other immune cells, as well as in myeloproliferative neoplasm (27)(28)(29)(30). In this study, we show that forced Notch activation in macrophages by conditional overexpressing Notch intracellular domain (NIC) was sufficient to support TAM differentiation but abrogate TAM functions, most likely through miR-125a, leading to repressed tumor growth in mice.…”

Section: Introductionmentioning

confidence: 99%

Forced Activation of Notch in Macrophages Represses Tumor Growth by Upregulating miR-125a and Disabling Tumor-Associated Macrophages

et al. 2016

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Tumor-associated macrophages (TAM) contribute greatly to hallmarks of cancer. Notch blockade was shown to arrest TAM differentiation, but the precise role and underlying mechanisms require elucidation. In this study, we employed a transgenic mouse model in which the Notch1 intracellular domain (NIC) is activated conditionally to define the effects of active Notch1 signaling in macrophages. NIC overexpression had no effect on TAM differentiation, but it abrogated TAM function, leading to repressed growth of transplanted tumors. Macrophage miRNA profiling identified a novel downstream mediator of Notch signaling, miR-125a, which was upregulated through an RBP-J-binding site at the first intronic enhancer of the host gene Spaca6A. miR-125a functioned downstream of Notch signaling to reciprocally influence polarization of M1 and M2 macrophages by regulating factor inhibiting hypoxia inducible factor-1a and IRF4, respectively. Notably, macrophages transfected with miR-125a mimetics increased phagocytic activity and repressed tumor growth by remodeling the immune microenvironment. We also identified a positive feedback loop for miR-125a expression mediated by RYBP and YY1. Taken together, our results showed that Notch signaling not only supported the differentiation of TAM but also antagonized their protumorigenic function through miR-125a. Targeting this miRNA may reprogram macrophages in the tumor microenvironment and restore their antitumor potential.

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“…Pan et al showed that miR-125a could stabilize both the commitment and immunoregulatory capacity of T reg . MiR-125a knock-out mice have been shown to be susceptible to autoimmune encephalomyelitis, because decreased expression of miR-125a disrupted T reg -mediated immune homeostasis leading to inflammation [39]. In addition, the genome-wide target analysis revealed that miR-125a could suppress expression of several genes, including STAT-3, IFN-g and IL-13, relative to effector T cell function.…”

Section: T Cell Subset Alterationmentioning

confidence: 99%

“…Data from a murine model also suggested that IL-21 signalling is fundamental to the pathogenesis of SLE. In addition, several studies have implicated that decreased expression of miR-410, miR-125a and miR-125b could contribute to the increased expression of STAT-3 [36,39,40] and STAT-3 is known to be important for Tfh cell differentiation. Finally, the miRNA cluster miR-17-92 appeared to be critical for Tfh cell differentiation and function [43,44].…”

Section: T Cell Subset Alterationmentioning

confidence: 99%

Immunopathogenesis of systemic lupus erythematosus and rheumatoid arthritis: the role of aberrant expression of non-coding RNAs in T cells

Lai

Koo

et al. 2017

Clinical and Experimental Immunology

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Summary Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are RNA molecules that do not translate into protein. Both miRNAs and lncRNAs are known to regulate gene expression and to play an essential role in T cell differentiation and function. Both systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disease, and rheumatoid arthritis (RA), a representative disease of inflammatory arthritis, are characterized by a complex dysfunction in the innate and adaptive immunity. T cells play a central role in cell-mediated immune response and multiple defects in T cells from patients with SLE and RA have been observed. Abnormality in T cell signalling, cytokine and chemokine production, T cell activation and apoptosis, T cell differentiation and DNA methylation that are associated closely with the aberrant expression of a number of miRNAs and lncRNAs have been implicated in the immunopathogenesis of SLE and RA. This review aims to provide an overview of the current state of research on the abnormal expression of miRNAs and lncRNAs in T cells and their roles in the immunopathogenesis of SLE and RA. In addition, by comparing the differences in aberrant expression of miRNAs and lncRNAs in T cells between patients with SLE and RA, controversial areas are highlighted that warrant further investigation.

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MiR-125a targets effector programs to stabilize Treg-mediated immune homeostasis

Cited by 119 publications

References 49 publications

Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

Forced Activation of Notch in Macrophages Represses Tumor Growth by Upregulating miR-125a and Disabling Tumor-Associated Macrophages

Immunopathogenesis of systemic lupus erythematosus and rheumatoid arthritis: the role of aberrant expression of non-coding RNAs in T cells

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