Identification of microRNA‐31 as a novel regulator contributing to impaired interleukin‐2 production in T cells from patients with systemic lupus erythematosus

Fan, Wei; Liang, Dong; Tang, Yue; Qu, Bo; Cui, Huijuan; Luo, Xiao-Jun; Huang, Xinfang; Chen, Shun‐le; Higgs, Brandon W.; Jallal, Bahija; Yao, Yihong; Harley, John B.; Shen, Nan

doi:10.1002/art.34596

Cited by 100 publications

(66 citation statements)

References 60 publications

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“…In addition, lupus-associated miRNAs are reported to be differentially expressed in male and female lupusprone NZB/NZW F1 mice (100). Lupus-associated miRNAs regulate the expression of a number of genes that are important for immune responses, including FOXP3, RHOA, FCGR1, and others (101)(102)(103)(104). It is not entirely clear what drives differential expression of miRNAs in males and females.…”

Section: Chromosome-encoded Micrornas In Sexual Dimorphismmentioning

confidence: 99%

Sexual dimorphism in autoimmunity

Rubtsova¹,

Marrack²,

Rubtsov³

2015

J. Clin. Invest.

170

127

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R e v i e w S e R i e S : A u t o i m m u n i t y 2 1 8 8jci.org Volume 125 Number 6 June 2015expression of IFN1 genes is controlled directly by sex hormones. On the other hand, sex hormones do affect expression of some of the PRRs (see below) and in this way might indirectly affect IFN1 levels. Thus, the abundance of IFN1s in lupus patients might be caused by female sex hormone-induced increases in PRR levels, which in turn increase production of IFN1s. One of the genes that controls expression of IFN1s is IFN regulatory factor 5 (IRF5). IRF5 has also been identified as a significant risk factor for lupus susceptibility (37,38). Expression of IRF5 in mice has been reported to be sex dependent (39). As demonstrated by Shen and colleagues (39), C57BL/6, NZB, Nba2, NZB/NZW F1, and NZM mouse strains express significantly higher levels of Irf5 mRNA in female than in male lymphocytes. Additionally, splenocytes from lupus-prone mice were shown to express higher levels of Irf5 mRNA compared with cells from the C57BL/6 strain, which is not prone to lupus. This group further demonstrated that Irf5 expression can be upregulated in vitro upon estrogen treatment, suggesting a potential mechanism for sex-biased expression of the gene and consequent overproduction of IFN1s (39).Absence of IFN-γ signaling protects NZB/NZW F1 mice against lupus-like disease (40). Expression of the IFNG gene, on the other hand, is regulated directly by estrogens (41)(42)(43)(44)(45). This finding suggests a positive feedback loop between the IFNs and estrogens, since activation of IFN1 or IFN-γ signaling upregulates the expression of ERα (46). Estrogen, in turn, promotes IFN-γ production by various lymphocytes. In addition, Panchanathan et al. demonstrated synergistic involvement of ERα and IFN signaling in activating the transcription of both IFN and estrogen-responsive target genes (46).Once produced, IFNs have many effects on the immune system that contribute to the sex bias of autoimmunity. For example, IFN1s increase class 1 MHC expression on cells, and IFN-γ induces class II MHC and changes the nature of the proteasome, thereby affecting the nature and quantity of self-peptides presented to T cells. Other examples are described below. Other immune-associated genes affected by sex hormonesMany genes with products that affect the immune system are controlled by sex hormones. As far as innate immunity is concerned, estrogens induce the expression of intracellular but not surface TLRs in both male and female PBMCs (23). Because intracellular TLRs have been shown to affect the development of autoimmunity (47-51), it is possible that the hormonal effect of the expression of intracellular TLRs contributes to female-biased autoimmunity.Unc-93 homolog B1 (UNC93B1) is an endoplasmic reticulum (ER) transmembrane protein that is essential for trafficking the TLRs that are expressed intracellularly (TLR3, TLR7, TLR8, TLR9, and probably other TLRs) from the ER to endosomes (52-54). UNC93B1 regulates the activity of these TLRs by mediating localization t...

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Section: Chromosome-encoded Micrornas In Sexual Dimorphismmentioning

confidence: 99%

Sexual dimorphism in autoimmunity

Rubtsova¹,

Marrack²,

Rubtsov³

2015

J. Clin. Invest.

170

127

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“…The regulation of il-2 is complex, but mir-31 and mir-155 contributes to its expression. Fan et al demonstrated that decreased mir-31 expression positively correlates with decreased il-2 synthesis in sle T cells 111 . Further experiments showed that mir-31 increases il-2 promoter activity by altering the expression of the nuclear factor of activated T cells (NFaT) (ref.…”

Section: Pathologies In Adaptive Immunity In Sle and Mirs T Cells MImentioning

confidence: 99%

“…as mentioned above, il-2 -a cytokine that is essential for Treg survivalis down-regulated by mir-31 or mir-155 in sle (ref. 111,112 ). moreover, mir-31 can suppress Foxp3 expression directly by binding to 3'UTr mrNa (ref.…”

mentioning

confidence: 99%

MicroRNAs in the key events of systemic lupus erythematosus pathogenesis

Hušáková¹

2016

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. Small non-coding RNA molecules (miRs) are involved in immune cell maturation and function and might influence immunopathological processes of systemic lupus erythematosus (SLE) pathogenesis. Methods and Results. This paper presents the results of a literature search for publications dealing with the relationship between miRs and pathological factors related to SLE such as genetic background, immune dysregulation and gender-associated differences participating in SLE development. In SLE, distinct miRs are differentially expressed in SLE cells of innate and adaptive immunity. The miR-146a and miR-155 genes, among others, interfere with intracellular signalling pathways downstream of toll-like receptors 7 and 9 (TLR-7, TLR-9) and influences interferon (IFN)-type I synthesis in plasmacytoid dendritic cells. In T and B cells, miR-126, miR-21, miR-146a, miR-155, miR-1246 and others might influence gene expression by epigenetic modifications, support abnormal cytosine release, differentiation of cell subsets, B cell hyperactivity and autoantibody production. Besides, estrogen might up-and downregulate immunologically active miRs, which are potential mediators of hormonal influences in SLE development. Moreover, SLE genetic basis included some polymorphisms of the miR-146a gene, which varies across populations. Conclusion. Distinct miRs are differentially expressed in both SLE mice models and human patients and promote autoimmune features of immune processes. MiRs are important molecules modulating susceptibility to SLE as well as its onset, clinical diversity and progression.

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“…Furthermore, it has been reported that regulation of miR‐31a‐5p expression could be used to modulate senescence‐related pathological conditions such as cancer, and the aging process (Capri et al., 2017; Cho, Dimri, & Dimri, 2015), which highlights us the important role of miR‐31a‐5p in cellular senescence. Moreover, according to a previous study, miR‐31a‐5p controls osteoclast formation and facilitates IL‐2 production in T cells by targeting RhoA (Fan et al., 2012; Mizoguchi, Murakami, Saito, Miyasaka, & Kohsaka, 2013). Thus, these findings raise the possibility that miR‐31a‐5p derived from BMSCs regulates both osteoblastogenesis and osteoclastogenesis.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐31a‐5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment

et al. 2018

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The alteration of age‐related molecules in the bone marrow microenvironment is one of the driving forces in osteoporosis. These molecules inhibit bone formation and promote bone resorption by regulating osteoblastic and osteoclastic activity, contributing to age‐related bone loss. Here, we observed that the level of microRNA‐31a‐5p (miR‐31a‐5p) was significantly increased in bone marrow stromal cells (BMSCs) from aged rats, and these BMSCs demonstrated increased adipogenesis and aging phenotypes as well as decreased osteogenesis and stemness. We used the gain‐of‐function and knockdown approach to delineate the roles of miR‐31a‐5p in osteogenic differentiation by assessing the decrease of special AT‐rich sequence‐binding protein 2 (SATB2) levels and the aging of BMSCs by regulating the decline of E2F2 and recruiting senescence‐associated heterochromatin foci (SAHF). Notably, expression of miR‐31a‐5p, which promotes osteoclastogenesis and bone resorption, was markedly higher in BMSCs‐derived exosomes from aged rats compared to those from young rats, and suppression of exosomal miR‐31a‐5p inhibited the differentiation and function of osteoclasts, as shown by elevated RhoA activity. Moreover, using antagomiR‐31a‐5p, we observed that, in the bone marrow microenvironment, inhibition of miR‐31a‐5p prevented bone loss and decreased the osteoclastic activity of aged rats. Collectively, our results reveal that miR‐31a‐5p acts as a key modulator in the age‐related bone marrow microenvironment by influencing osteoblastic and osteoclastic differentiation and that it may be a potential therapeutic target for age‐related osteoporosis.

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Identification of microRNA‐31 as a novel regulator contributing to impaired interleukin‐2 production in T cells from patients with systemic lupus erythematosus

Cited by 100 publications

References 60 publications

Sexual dimorphism in autoimmunity

Sexual dimorphism in autoimmunity

MicroRNAs in the key events of systemic lupus erythematosus pathogenesis

MicroRNA‐31a‐5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment

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