MiRNAs and inflammatory bowel disease: An interesting new story

Inflammatory bowel disease (IBD), as a chronic and recurrent inflammatory disorder, is caused by a dysregulated and aberrant immune response to exposed environmental factors in genetically susceptible individuals. Despite huge efforts in determining the molecular pathogenesis of IBD, an increasing worldwide incidence of IBD has been reported. MicroRNAs (miRNAs) are a set of noncoding RNA molecules that are about 22 nucleotides long, and these molecules are involved in the regulation of the gene expression. By clarifying the important role of miRNAs in a number of diseases, their role was also considered in IBD; numerous studies have been performed on this topic. In this review, we attempt to summarize a number of studies and discuss some of the recent developments in the roles of miRNAs in the pathophysiology, diagnosis, and treatment of IBD.     

microRNAs参与动脉粥样硬化疾病的发生

microRNAs (miRNAs)是一类非编码的小分子RNA（～22 nt）,可在转录后水平调控基因表达.miRNAs参与调控机体的多种生理和病理过程.近来研究表明,miRNAs可能与动脉粥样硬化疾病的发生和发展密切相关,在血管新生、炎症和脂蛋白代谢等方面发挥了关键作用.本文就miRNAs与动脉粥样硬化疾病相关的研究进展进行综述,为研究miRNAs在动脉粥样硬化的发病机制中的作用,以及为miRNAs能够作为诊断动脉粥样硬化疾病的生物标志物提供思路.     

MicroRNAs: the fine-tuners of Toll-like receptor signalling

Toll-like receptor (TLR) signalling must be tightly regulated to avoid excessive inflammation and to allow for tissue repair and the return to homeostasis after infection and tissue injury. MicroRNAs (miRNAs) have emerged as important controllers of TLR signalling. Several miRNAs are induced by TLR activation in innate immune cells and these and other miRNAs target the 3' untranslated regions of mRNAs encoding components of the TLR signalling system. miRNAs are also proving to be an important link between the innate and adaptive immune systems, and their dysregulation might have a role in the pathogenesis of inflammatory diseases.     

Neurotrophins in inflammatory lung diseases: modulators of cell differentiation and neuroimmune interactions

Chronic inflammatory lung diseases represent a group of severe diseases with increasing prevalence as well as epidemiological importance. Inflammatory lung diseases could result from allergic or infectious genesis. There is growing evidence that the immune and nervous system are closely related not only in physiological but also in pathological reactions in the lung. Extensive communications between neurons and immune cells are responsible for the magnitude of airway inflammation and the development of airway hyperreactivity, a consequence of neuronal dysregulation. Neurotrophins are molecules regulating and controlling this crosstalk between the immune and peripheral nervous system (PNS) during inflammatory lung diseases. They are constitutively expressed by resident lung cells and produced in increasing quantities by immune cells invading the airways under inflammatory conditions. They act as activation, differentiation and survival factors for cells of both the immune and nervous system. This article will review the most recent data of neurotrophin signaling in the normal and inflamed lung and as yet unexplored, roles of neurotrophins in the complex communication within the neuroimmune network.     

Exploiting the therapeutic potential of microRNAs in viral diseases: expectations and limitations

New therapeutic approaches are urgently needed for serious diseases, including cancer, cardiovascular diseases, viral infections, and others. A recent direction in drug development is the utilization of nucleic acid-based therapeutic molecules, such as antisense oligonucleotides, ribozymes, short interfering RNA (siRNA), and microRNA (miRNA). miRNAs are endogenous, short, non-coding RNA molecules. Some viruses encode their own miRNAs, which play pivotal roles in viral replication and immune evasion strategies. Conversely, viruses that do not encode miRNAs may manipulate host cell miRNAs for the benefits of their replication. miRNAs have therefore become attractive tools for the study of viral pathogenesis. Lately, novel therapeutic strategies based on miRNA technology for the treatment of viral diseases have been progressing rapidly. Although this new generation of molecular therapy is promising, there are still several challenges to face, such as targeting delivery to specific tissues, avoiding off-target effects of miRNAs, reducing the toxicity of the drugs, and overcoming mutations and drug resistance. In this article, we review the current knowledge of the role and therapeutic potential of miRNAs in viral diseases, and discuss the limitations of these therapies, as well as strategies to overcome them to provide safe and effective clinical applications of these new therapeutics.     

Characterization of miRNAs involved in response to poly(I:C) in porcine airway epithelial cells

MicroRNAs (miRNA) have been implicated in a variety of pathological conditions including infectious diseases. Knowledge of the miRNAs affected by poly(I:C), a synthetic analog of viral double‐stranded RNA, in porcine airway epithelial cells (PAECs) contributes to understanding the mechanisms of swine viral respiratory diseases, which bring enormous economic loss worldwide every year. In this study, we used high throughput sequencing to profile miRNA expression in PAECs treated with poly(I:C) as compared to the untreated control. This approach revealed 23 differentially expressed miRNAs (DEMs), five of which have not been implicated in viral infection before. Nineteen of the 23 miRNAs were down‐regulated including members of the miR‐17‐92 cluster, a well‐known polycistronic oncomir and extensively involved in viral infection in humans. Target genes of DEMs, predicted using bioinformatic methods and validated by luciferase reporter analysis on two representative DEMs, were significantly enriched in several pathways including transforming growth factor‐β signaling. A large quantity of sequence variations (isomiRs) were found including a substitution at position 5, which was verified to redirect miRNAs to a new spectrum of targets by luciferase reporter assay together with bioinformatics analysis. Twelve novel porcine miRNAs conserved in other species were identified by homology analysis together with cloning verification. Furthermore, the expression analysis revealed the potential importance of three novel miRNAs in porcine immune response to viruses. Overall, our data contribute to clarifying the mechanisms underlying the host immune response against respiratory viruses in pigs, and enriches the repertoire of porcine miRNAs.     

DNA甲基化与microRNA

细胞中DNA甲基化和microRNA（miRNA）相互影响,并共同调控着下游靶基因的表达活性,在细胞生长代谢、免疫、肿瘤和心血管疾病等生理和病理过程中发挥重要作用。首先简要介绍DNA甲基化与miRNA的概况,然后分析了miRNA调控下的DNA甲基化改变,探讨了DNA甲基化影响miRNA的表达活性变化,并归纳了miRNA与DNA甲基化之间的反馈调控关系;最后对DNA甲基化和miRNA的应用前景进行了简单探讨。研究DNA甲基化与miRNA间的网络调控关系,可为表观调控机制在理论和实践中的深入研究和应用提供参考。     

Notch signaling and its emerging role in autoimmunity

Studies of notch signaling in immune cells have uncovered critical roles for this pathway both during the differentiation and effector function phases of immune responses. Cells of the myeloid lineage, including macrophages and dendritic cells, function as key components of innate immune defense against infection and, by acting as antigen presenting cells, can instruct cells of the adaptive immune response, specifically CD4 and CD8 T cells. Tight regulation of this functional interaction is needed to ensure a well-balanced immune response and its dysregulation may indirectly or directly cause the tissue damage characteristic of autoimmune diseases. In this review, the focus will be placed on those recent findings which support a role for notch signaling in inflammatory responses mediated by macrophages and other myeloid lineage cells, as well as peripheral T cells, and their relevance to inflammatory and autoimmne diseases.     

Identification of microRNAs associated with allergic airway disease using a genetically diverse mouse population

Background

Allergic airway diseases (AADs) such as asthma are characterized in part by granulocytic airway inflammation. The gene regulatory networks that govern granulocyte recruitment are poorly understood, but evidence is accruing that microRNAs (miRNAs) play an important role. To identify miRNAs that may underlie AADs, we used two complementary approaches that leveraged the genotypic and phenotypic diversity of the Collaborative Cross (CC) mouse population. In the first approach, we sought to identify miRNA expression quantitative trait loci (eQTL) that overlap QTL for AAD-related phenotypes. Specifically, CC founder strains and incipient lines of the CC were sensitized and challenged with house dust mite allergen followed by measurement of granulocyte recruitment to the lung. Total lung RNA was isolated and miRNA was measured using arrays for CC founders and qRT-PCR for incipient CC lines.

Results

Among CC founders, 92 miRNAs were differentially expressed. We measured the expression of 40 of the most highly expressed of these 92 miRNAs in the incipient lines of the CC and identified 18 eQTL corresponding to 14 different miRNAs. Surprisingly, half of these eQTL were distal to the corresponding miRNAs, and even on different chromosomes. One of the largest-effect local miRNA eQTL was for miR-342-3p, for which we identified putative causal variants by bioinformatic analysis of the effects of single nucleotide polymorphisms on RNA structure. None of the miRNA eQTL co-localized with QTL for eosinophil or neutrophil recruitment. In the second approach, we constructed putative miRNA/mRNA regulatory networks and identified three miRNAs (miR-497, miR-351 and miR-31) as candidate master regulators of genes associated with neutrophil recruitment. Analysis of a dataset from human keratinocytes transfected with a miR-31 inhibitor revealed two target genes in common with miR-31 targets correlated with neutrophils, namely Oxsr1 and Nsf.

Conclusions

miRNA expression in the allergically inflamed murine lung is regulated by genetic loci that are smaller in effect size compared to mRNA eQTL and often act in trans. Thus our results indicate that the genetic architecture of miRNA expression is different from mRNA expression. We identified three miRNAs, miR-497, miR-351 and miR-31, that are candidate master regulators of genes associated with neutrophil recruitment. Because miR-31 is expressed in airway epithelia and is predicted to target genes with known links to neutrophilic inflammation, we suggest that miR-31 is a potentially novel regulator of airway inflammation.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1732-9) contains supplementary material, which is available to authorized users.     

MicroRNAs in inflammatory lung disease - master regulators or target practice?

MicroRNAs (miRNAs) have emerged as a class of regulatory RNAs with immense significance in numerous biological processes. When aberrantly expressed miRNAs have been shown to play a role in the pathogenesis of several disease states. Extensive research has explored miRNA involvement in the development and fate of immune cells and in both the innate and adaptive immune responses whereby strong evidence links miRNA expression to signalling pathways and receptors with critical roles in the inflammatory response such as NF-κB and the toll-like receptors, respectively. Recent studies have revealed that unique miRNA expression profiles exist in inflammatory lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis and lung cancer. Evaluation of the global expression of miRNAs provides a unique opportunity to identify important target gene sets regulating susceptibility and response to infection and treatment, and control of inflammation in chronic airway disorders. Over 800 human miRNAs have been discovered to date, however the biological function of the majority remains to be uncovered. Understanding the role that miRNAs play in the modulation of gene expression leading to sustained chronic pulmonary inflammation is important for the development of new therapies which focus on prevention of disease progression rather than symptom relief. Here we discuss the current understanding of miRNA involvement in innate immunity, specifically in LPS/TLR4 signalling and in the progression of the chronic inflammatory lung diseases cystic fibrosis, COPD and asthma. miRNA in lung cancer and IPF are also reviewed.     

An update: Epstein-Barr virus and immune evasion <Emphasis Type="Italic">via</Emphasis> microRNA regulation

Epstein-Barr virus (EBV) is an oncogenic virus that ubiquitously establishes life-long persistence in humans. To ensure its survival and maintain its B cell transformation function, EBV has developed powerful strategies to evade host immune responses. Emerging evidence has shown that microRNAs (miRNAs) are powerful regulators of the maintenance of cellular homeostasis. In this review, we summarize current progress on how EBV utilizes miRNAs for immune evasion. EBV encodes miRNAs targeting both viral and host genes involved in the immune response. The miRNAs are found in two gene clusters, and recent studies have demonstrated that lack of these clusters increases the CD4⁺ and CD8⁺ T cell response of infected cells. These reports strongly indicate that EBV miRNAs are critical for immune evasion. In addition, EBV is able to dysregulate the expression of a variety of host miRNAs, which influence multiple immune-related molecules and signaling pathways. The transport via exosomes of EBV-regulated miRNAs and viral proteins contributes to the construction and modification of the inflammatory tumor microenvironment. During EBV immune evasion, viral proteins, immune cells, chemokines, pro-inflammatory cytokines, and pro-apoptosis molecules are involved. Our increasing knowledge of the role of miRNAs in immune evasion will improve the understanding of EBV persistence and help to develop new treatments for EBV-associated cancers and other diseases.

Open image in new window

     

Immune modulatory function of abundant immune-related microRNAs in microvesicles from bovine colostrum

Colostrum provides essential nutrients and immunologically active factors that are beneficial to newborns. Our previous work demonstrated that milk contains large amounts of miRNA that is largely stored in milk-derived microvesicles (MVs). In the present study, we found that the MVs from colostrum contain signifi cantly higher levels of several immune-related miRNAs. We hypothesized that the colostrum MVs may transfer the immune-related miRNAs into cells, which contribute to its immune modulatory feature. We isolated colostrum MVs by ultracentrifugation and demonstrated several immune modulation features associated with miRNAs. We also provide evidence that the physical structure of milk-derived MVs is essential for transfer miRNAs and following immune modulation effect. Moreover, we found that colostrum powder-derived MVs also contains higher levels of immune-related miRNAs that display similar immune modulation effects. Taken together, these results show that MV-containing immunerelated miRNAs may be a novel mechanism by which colostrum modulates body immune response.