miRNAs In Immune Response Research Articles

Analysis of miRNA expression in the trachea of Ri chicken infected with the highly pathogenic avian influenza H5N1 virus.

Highly pathogenic avian influenza virus (HPAIV) is considered a global threat to both human health and the poultry industry. MicroRNAs (miRNA) can modulate the immune system by affecting gene expression patterns in HPAIV-infected chickens. To gain further insights into the role of miRNAs in immune responses against H5N1 infection, as well as the development of strategies for breeding disease-resistant chickens, we characterized miRNA expression patterns in tracheal tissues from H5N1-infected Ri chickens. miRNAs expression was analyzed from two H5N1-infected Ri chicken lines using small RNA sequencing. The target genes of differentially expressed (DE) miRNAs were predicted using miRDB. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis were then conducted. Furthermore, using quantitative real-time polymerase chain reaction, we validated the expression levels of DE miRNAs (miR-22-3p, miR-146b-3p, miR-27b-3p, miR-128-3p, miR-2188-5p, miR-451, miR-205a, miR-203a, miR-21-3p, and miR-200a-3p) from all comparisons and their immune-related target genes. A total of 53 miRNAs were significantly expressed in the infection samples of the resistant compared to the susceptible line. Network analyses between the DE miRNAs and target genes revealed that DE miRNAs may regulate the expression of target genes involved in the transforming growth factor-beta, mitogen-activated protein kinase, and Toll-like receptor signaling pathways, all of which are related to influenza A virus progression. Collectively, our results provided novel insights into the miRNA expression patterns of tracheal tissues from H5N1-infected Ri chickens. More importantly, our findings offer insights into the relationship between miRNA and immune-related target genes and the role of miRNA in HPAIV infections in chickens.

Circulating miR-155, a potential regulator of immune responses to different vaccines in chicken

Vaccination is one of effective means to prevent viral infectious diseases in poultry. However, the functions of circulating miRNAs in immune response remain unknown. In this study, miR-155, a key factor in the regulation of immune function, was selected to study its expression, potential function and mechanism in the 12-day-old chicken immune responses to three vaccines (avian influenza virus inactivated vaccine, Newcastle disease virus attenuated vaccine and infectious bursal disease virus attenuated vaccine), respectively. The experiment aimed to explore the relationships between the expression levels of serum circulating miR-155 and immune responses. The results showed that the expression levels of serum circulating miR-155 were significantly different during the three immune responses, but had similarities at several time points post inoculation. 2 day post inoculation (dpi), 5dpi, and 21dpi were the possible common key time points of the three immune responses. Moreover, spleen (2dpi), bursa of Fabricius and cecal tonsil (5dpi), and liver (21dpi) were the possible key tissues associated with the differential expression levels of serum circulating miR-155. Bioinformatics analysis showed that several key target genes (such as KRAS, RAP1B, and RPS6KA3) of miR-155 possibly played a key role in immune function regulation through MAPK and mTOR signaling pathways. The study can lay the foundation for further studying the function and application of circulating miR-155 in chicken immune responses.

MiRNA as a Modulator of Immunotherapy and Immune Response in Melanoma.

Immune checkpoint inhibitors are a promising therapy for the treatment of cancers, including melanoma, that improved benefit clinical outcomes. However, a subset of melanoma patients do not respond or acquire resistance to immunotherapy, which limits their clinical applicability. Recent studies have explored the reasons related to the resistance of melanoma to immune checkpoint inhibitors. Of note, miRNAs are the regulators of not only cancer progression but also of the response between cancer cells and immune cells. Investigation of miRNA functions within the tumor microenvironment have suggested that miRNAs could be considered as key partners in immunotherapy. Here, we reviewed the known mechanism by which melanoma induces resistance to immunotherapy and the role of miRNAs in immune responses and the microenvironment.

Under-expression of microRNA-146a and 21 and their association with Crohn's disease.

MicroRNAs (miRNAs) can post-transcriptionally regulate gene expression and are involved in the immune response. Excessive immune response to the gut microbiota plays a major role in the pathogenesis of Crohn's disease (CD). Regarding the role of miRNAs in immune response, this study aimed to investigate the contribution of miRNAs in the pathogenesis of CD. A total of 53 participants, including 23 CD patients and 30 healthy controls (HCs) were enrolled in this study. miRNAs, including miR-21, miR-29a, miR-29b, miR-31, miR-146a, miR-155, miR-181a, and miR-181c were evaluated via TaqMan MicroRNA Assays. Among the eight miRNAs, the amounts of miR-146a and miR-21 were significantly decreased in the CD patients relative to HC subjects. Moreover, we showed that there was a negative correlation between miR-146a and Harvey-Bradshaw index (HBI), as well as a positive correlation of miR-21 and miR-29b with HBI. Under-expression of miR-146a and miR-21, which are critical for the regulatory function of regulatory T cells (Tregs), is remarkably associated with CD.

Role of miRNAs in immune responses and immunotherapy in cancer.

In the past decade, the study of mechanisms of cancer immunity has seen a prominent boom, which paralleled the increased amount of research on the clinical efficacy of immune checkpoint blockade in several lethal types of cancers. This conspicuous effort has led to the development of successful immunotherapy treatment strategies, whose medical impact has been recognized by the awarding of 2018 Nobel Prize in Physiology or Medicine to the two pioneers of check point inhibitor research, Tasuku Honjo and James Allison. Despite these promising achievements, the differences in the clinical response rate in different cancer patients and the high risk of toxicity of immune-based therapies represent crucial challenges. More remarkably, the causes responsible for different outcome (success vs failure) in patients with tumor having same histotype and clinical characteristics remain mostly unknown. MicroRNAs (miRNAs), small regulatory noncoding RNA molecules representing the most studied component of the dark matter of the human genome, are involved in the regulation of many pathways of cancer and immune cells. Therefore, understanding the role of miRNAs in controlling cancer immunity is necessary, as it can contribute to reveal mechanisms that can be modulated to improve the success of immunetherapy in cancer patients. Here, we discuss the latest findings on immune pathways regulated by miRNAs in cancer, miRNA-mediated regulation of immune cells in the tumor microenvironment, and miRNAs as potential target for immunotherapies.

MiRNAs in immune responses to Mycobacterium tuberculosis infection

Tuberculosis (TB) is one of the most fatal infectious diseases, affecting one third of the world's population. The causative agent, Mycobacterium tuberculosis (Mtb), has a well-established ability to circumvent the host's immune system for its long-term intracellular survival. MicroRNAs (miRNAs) are crucial post-transcriptional regulators of immune response. They act by negatively regulating the expression levels of important genes in both innate and adaptive immunity. It has been established in recent studies that the host immune response against Mtb is regulated by many miRNAs, most of which are induced by Mtb infection. Moreover, differential expression of miRNA in tuberculosis (TB) patients may help distinguish between TB patients and healthy individuals or latent TB. In this review, we present the recent advancements on the miRNA regulation of the host responses against Mtb infection, as well as the potential of miRNAs to as biomarkers for TB diagnosis.

Exosomal miRNAs regulate inflammatory responses (IRM11P.624)

Abstract MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Typically, miRNAs are thought to function within the cells where they are transcribed. However, recent data shows that miRNAs are transferred between cells and mediate target gene repression. miR-155 and miR-146a are critical miRNAs that regulate inflammation. We found that miR-155 and miR-146a were released from dendritic cells (DCs) within exosomes and transferred to recipient DCs. These miRNAs were associated with RISC and inhibited their mRNA targets in recipient cells. Following uptake, miRNAs reprogramed the cellular response to endotoxin, where exosomal miR-155 enhanced and miR-146a reduced inflammatory gene expression. miR-155 and miR-146a were also found in exosomes and passed between immune cells in vivo. Additionally, injection of miR-146a containing exosomes delivered miR-146a to various tissues and decreased inflammation in response to endotoxin, while miR-155 containing exosomes had the converse effect. This suggests that exosomal miRNAs could be used as therapy for inflammatory diseases. Further characterization of the loading and functional transfer of miRNAs should make therapeutic approaches more feasible. Additionally, we aim to explore the importance of endogenously transferred miRNAs during immune responses in vivo. Our research will help unravel both the therapeutic potential of exosomal miRNAs and determine the biological relevance of transferred miRNAs in immune responses.

Human leukocyte antigen G and miR-148a are associated with the pathogenesis of intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) occurs mainly during the third trimester of gestation and is characterized by pruritus and elevated serum bile acid levels. The pathogenesis of this disease has yet to be elucidated. The nonclassical human leukocyte antigen G (HLA-G) is a trophoblast-specific molecule and is involved in the regulation of maternal immune response at the maternal-fetal interface. MicroRNAs (miRNAs) have an important role in a number of physiological and pathological processes. However, the roles of HLA-G and miRNAs in immune response in the pathogenesis of ICP have yet to be elucidated. In the present study, the expression of HLA-G and miR-148a in the placenta of patients with ICP was investigated. The mRNA and protein expression levels of HLA-G were markedly reduced in the placenta of patients with ICP compared with the levels in healthy pregnant females, and were negatively correlated with serum total bile acid (TBA) levels. It was also observed that miR-148a levels were markedly upregulated in the placenta and peripheral blood of patients with ICP. Furthermore, the mRNA and protein expression levels of HLA-G in the placenta were negatively correlated with the miR-148 levels in the placenta, but not in the peripheral blood, while the miR-148a levels in the placenta were positively correlated with serum TBA levels. These results suggest that the downregulation of HLA-G is probably caused by the upregulation of miR-148a in the placenta, and miR-148a in the placenta may contribute to the pathogenesis of ICP via the inhibition of HLA-G expression.

163: Sequence-dependent off-target inhibition of TLR7/8 by synthetic microRNA inhibitors

Anti-microRNA (miRNA) oligonucleotides (AMOs) are commonly used to study miRNA function and present clear therapeutic potential. 2′-O-methyl (2′Ome) modified AMOs are among the most popular AMOs and can be modified to achieve high potency, high specificity and low cytoxicity. Nonetheless, 2′Ome oligonucleotide modification has previously been associated with an inhibitory activity on the sensing of pathogenic RNAs by innate immune sensors Toll-like receptor 7 and 8 (TLR7/8). In this work, we report on the ability of 2′Ome AMOs to inhibit TLR7 sensing of RNA in a sequence-dependent manner, independent of their miRNA-targeting function. Through a screen of 30 AMOs targeting common miRNAs, we found a subset of highly inhibitory sequences in mouse macrophages. Interspecies conservation of inhibitory activity on TLR7/8 was confirmed in human peripheral blood mononuclear cells – with an IC 50 activity as low as 2 nmol/l. Critically, we identified a core motif governing the inhibitory activity of these AMOs, which is present in more than 70 AMOs targeted to human miRNAs in miRBaseV20. DNA/LNA AMOs synthesised with a phosphorothioate backbone also inhibited TLR7 in a sequence-dependent manner, demonstrating that the off-target effects of AMOs on TLR7/8 are not restricted to 2′Ome AMOs. Collectively, our work establishes the potential for off-target effects of AMOs on TLR7/8 function, which should be taken into account when studying the role of miRNAs in immune responses.