|
 
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| REVIEW ARTICLE |
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| Year : 2013 | Volume
: 27
| Issue : 1 | Page : 3-8 |
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Involvement of microRNA in Asthma: New perspective in respiratory biology
Balaram Ghosh
Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma and Lung Disease, Council of Scientific and Industrial Research (CSIR)-Institute of Genomics and Integrative Biology, Delhi
| Date of Web Publication | 17-Aug-2013 |
Correspondence Address:
Balaram Ghosh
Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma and Lung Disease, Council of Scientific and Industrial Research (CSIR)-Institute of Genomics and Integrative Biology, Mall Road, Delhi - 110 007
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0972-6691.116603
A new insights have come from studies in Caenorhabditis elegans, in which researchers have identified a new endogenous class of small noncoding RNA (22-25 nucleotides), termed as microRNAs (miRNAs) as developmental regulators. Here, we discuss some recent studies demonstrating the role of miRNAs in asthma, with the anticipation that these studies were likely to influence treatment, diagnosis, and management of asthma and other inflammatory disorders. use of miRNAs as a therapy, the use of miRNAs holds great promise as a new treatment. Future of miRNA-based therapy in case of pulmonary disorders, such as asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) seems to be promising as indicated by animal studies. Keywords: Asthma, interleukin-10, interleukin-13, Let-7, microRNA, miR-106a
How to cite this article:
Ghosh B. Involvement of microRNA in Asthma: New perspective in respiratory biology. Indian J Allergy Asthma Immunol 2013;27:3-8 |
How to cite this URL:
Ghosh B. Involvement of microRNA in Asthma: New perspective in respiratory biology. Indian J Allergy Asthma Immunol [serial online] 2013 [cited 2023 Mar 29];27:3-8. Available from: https://www.ijaai.in/text.asp?2013/27/1/3/116603 |
| Introduction | |  |
Asthma is a serious public health problem and it is estimated to affect more than 350 million people throughout the world, particularly in developing countries like India where approximately 7-10% population is affected by bronchial asthma. [1] Asthma affects individuals of all age groups, but in the majority of patients, the first symptoms start at a very young age. Symptoms of wheezing, breathlessness, chest tightness, and cough often occur following exposure to allergens such as house dust mite (HDM), fungi, or pollen. [2] Inhaler therapy with bronchodilators mostly improve these symptoms, however, a significant proportion of the responders progressively develop resistance towards commonly used bronchodilators including steroid inhalers, increasing the rate of morbidity, and mortality associated with asthma. [3] Thus, it becomes imperative to identify new modalities for developing better therapeutics for asthma.
Recently, new insights have come from studies in Caenorhabditis elegans, in which researchers have identified a new endogenous class of small noncoding RNA (22-25 nucleotides), termed as microRNAs (miRNAs) as developmental regulators. [4] The process of its biogenesis and function has been briefly outlined in [Figure 1]. These molecules were discovered in human in the last decade, where it was shown to modulate diverse physiological processes including hematopoietic lineage differentiation, angiogenesis, cell adhesion, and many more; by the posttranscriptional regulation of gene expression. [5],[6],[7],[8] A number of review articles published elsewhere have been focused on the biogenesis of miRNA and elaborated on their role in health and disease. However, the miRNA research is still in its infancy with respect to asthma. [9],[10],[11],[12],[13] Here, we discuss some recent studies demonstrating the role of miRNAs in asthma, with the anticipation that these studies were likely to influence treatment, diagnosis, and management of asthma and other inflammatory disorders. We also explore the tenets of this multifactorial disorder to explain the recent findings. | Figure 1: Biogenesis and functions of microRNA (miRNA). Most miRNAs transcribed by RNA polymerase II (pol II) yield primary transcripts called pri-miRNA, that are usually several kilobases long and contain a local hairpin structure which is recognized by Drosha-DGCR8. Primary transcript generated by Drosha-DGCR8 cleavage is transported by exportin-5 into the cytoplasm where another RNase III enzyme "dicer" cleaved primary transcript and yield a final 22-nucleotide double stranded miRNA. One strand of the duplex preferentially incorporated into RNA-induced silencing complex (RISC) containing AGO1-4, while the other gets degraded. Mature miRNA-AGO complex either promotes translation repression and deadenylation, or leads to mRNA degradation by endonucleolytic cleavage
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| TH1/TH2 Paradigm in Asthma | | |
Asthma is a multifactorial disorder, involving both genetic and environmental components. Most of the pathophysiological features of asthma are due to the infiltration of mononuclear cells, resulting in the imbalance of Th1/Th2 paradigm. [14] Increase in the number of CD4 + T helper 2 cells (Th2) in the asthmatic airways is well documented with elevated levels of cytokines, such as interleukin (IL)-4, IL-5, IL-13, and IL-9 and also allergen specific serum immunoglobulin E (IgE) and various chemokines. [15],[16] IL-4 and IL-13 are required to stimulate class switching to IgE in B cells. [17] IL-5 is responsible for the differentiation and subsequent migration of eosinophils to the lungs; while, IL-9 promotes the differentiation of mast cells. [18],[19] Besides Th-2, recently other T-helper subsets such as Th-17 in the development of steroid resistant neutrophilic asthma were suggested. [20] On the other hand, T-regulatory (T-regs) subsets were known to antagonize allergic inflammation by secreting cytokines like TGF-β and IL-10. [21] The fact that activation and inhibition of paracrine factors, that is, cytokines; released from different T helper subsets could affect asthma pathophysiology, has led researchers to investigate its underlying controlling mechanism. Differentiation of T-naive cells into specific T-subsets involves activation of specific transcription factor, for example, T-bet drives Th-1, GATA-3 promotes Th-2 differentiation, RORϒT helps in Th-17 differentiation, and FOXP3 promotes T-reg cells. [22] Growing literature also suggests key roles of epigenetic factors such as miRNA in the regulation of T-cell differentiation and control of cytokine expression.
| MIR-106A Regulates IL-10 and Alleviates Allergic Phenotype | | |
IL-10 is an immune modulatory cytokine responsible for maintaining immune homeostasis. Numerous reports have shown that dysregulation of IL-10 leads to various immunological diseases, such as cancer, rheumatoid arthritis, asthma, infectious disorders, etc. [23],[24],[25] IL-10 expression is regulated at the transcriptional, posttranscriptional, and epigenetic levels. Earlier, results observed discrepancies in the levels of IL-10 transcripts and IL-10 proteins. [26] Together with these results along with its critical roles in immune homeostasis, it is imperative that IL-10 expression is tightly regulated. Therefore, a pellucid understanding of the mechanisms by which IL-10 is regulated will be of great scientific and clinical significance.
Animal models of asthma suggest a complex role of IL-10 in asthma. IL-10 knockout mice have shown higher inflammation and increased airway hyperresponsiveness (AHR). [27] Also, intratracheal instillation of adenoviral vector over expressing IL-10 reduced AHR and infiltration of inflammatory cells in the lungs of mice with experimentally induced asthma. [28] In another but related study, it has been shown that intratracheal administration of IL-10 reduced AHR and airway inflammation. [29] It is well documented that alveolar macrophages from asthmatics produce relatively lower IL-10. [30] More importantly asthmatics produce relatively lower levels of IL-10 in the sputum and sera both in case of mild and severe asthma. [31]
In order to identify miRNA which may regulate and fine tune IL-10 expression, our group taking lead from both bioinformatics and experimental approaches identified a miRNA, miR-106a, which regulates IL-10 expression. [32] Further, elevated levels of IL-10 negatively correlate with miR-106a in IL-10 producing cell lines like Jurkat (T-cells) and Raji cells (B-cells). A series of transfection experiments in this study demonstrated that hsa-miR-106a significantly downregulated the expression of IL-10. Interestingly, hsa-miR-106b, which differs from hsa-miR-106a in only two nucleotide positions, also affected IL-10 expression albeit at a lower level. To understand the mechanism of miR106a regulation, we demonstrated that the level of miR-106a is transcriptionally regulated by early growth response-1 (Egr-1) under inflammatory condition. Bioinformatics analysis of the putative promoter region predicts overlapping binding sites for two transcription factors, Egr1 and Sp1. The interaction of Egr1 at the promoter of hsa-miR-106a was able to increase the expression of both pre and mature forms of hsa-miR-106a in a time dependent manner, which inversely correlated with the levels of IL-10.
The physiological relevance of miR-106a mediated posttranscriptional regulation of IL-10 has come from ovalbumin (OVA)-induced asthma model. Nearly three-fold increase of miR-106a levels was found to be inversely correlated with the lower levels of IL-10 expression in the lungs of OVA-induced mice model of asthma [Figure 2]. However, treatment with anti-mmu-miR-106a restored the level of IL-10 in the lungs of asthmatic mice. Interestingly, this treatment significantly educed airway inflammation, mucus metaplasia, and collagen deposition in the lungs of mice with experimentally induced asthma. It also reduced Th2 cytokine IL-4 and OVA specific antibodies IgG1 and IgE, and restored IgG2a. Finally, anti-mmu-miR-106a significantly restored AHR in asthmatic mice. These results suggest therapeutic potential of miR-106a in asthma and other inflammatory diseases where IL-10 plays a critical role. [33] | Figure 2: Knock-down of mmu-mir-106a upregulates interleukin (IL)-10 and attenuates asthma features. IL-10 is known for its immunosuppressive properties. Allergen sensitization and challenge-induced stress upregulates early growth response (Egr-1) protein, which transcribed miR-106-363 locus on X-chromosome and up regulates the level of miR-106a. Increased miR-106a levels posttranscriptionally downregulate IL-10 levels and increases inflammatory response in mice, that is characterized by upregulation of T-helper-2 (Th-2) cytokines like IL-4, IL-13, IL-5, and IgE production from B-cells. This, in turn, results in increase in asthmatic features such as inflammation, mucus secretion, subepithelial fibrosis, and airway hyperresponsiveness (AHR). In contrast, knockdown of miR-106a levels by miR-106a inhibitor upregulates IL-10 and reduces Th-2 cytokines levels along with asthmatic features
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| Let-7 Regulates IL-13 Expression During Allergic Inflammation | | |
IL-13 is considered as a central mediator of allergic asthma as its administration alone could mimic most of the features of asthma; and therefore, strategies manipulating its levels or signaling were under intensive research. [34] Elevated levels of IL-13 mRNA and protein present in the lungs of atopic and nonatopic asthmatics suggested that IL-13 increase may predispose individuals towards the development of asthma. [35] Population based studies have linked human asthma to a region on chromosome 5q and to single nucleotide polymorphism (SNPs) in the IL-13 gene. [36] Both IL-4 and IL-13 bind to common receptors and thus show functional redundancy; however conditional mutation in IL-4 and IL-13 shows that IL-4 is essential for the initial Th2 priming, whereas IL-13 has effector functions and is essential for the induction of tissue fibrosis, mucus production, and AHR. [37],[38],[39] Taken together, the mouse and human studies suggest the critical role of IL-13 in the development of asthma and related disorders.
IL-13 transcription is well studied in stimulated T-cells and is regulated by transcription factors NFAT and GATA-3. [40],[41] Besides transcriptional regulation, IL-13 is posttranscriptionally stabilized by HuR (Hu antigen R; RNA binding protein, RBP) under stress conditions. [42] We recently identified Let-7 miRNA as a posttranscriptional regulator of IL-13 in primary lymphocytes. [43] Let-7 miRNA family also known as tumor suppressor miRNAs and are downregulated in activated T-cells which negatively correlates with the release of IL-13 from these cells; suggesting that Let-7 mimics would attenuate asthma features, while Let-7 antagomirs should worsen the asthma phenotype. However, in separate studies, both Let-7 mimics and Let-7 antagomirs seem to inhibit the asthma features in OVA-induced experimental mice model of asthma, while some of recent data suggests that Let-7 expression reciprocally regulates IL-13 and its signaling. [43],[44] We observed an overall downregulation of various Let-7 members in allergically inflamed lungs. Interestingly, exogenous administration of Let-7 mimics in OVA-sensitized and challenged mice downregulate IL-13 and associated phenotype such as airway inflammation, mucus metaplasia, collagen deposition, and AHR [Figure 3]. Further, miRNA profiling of the exosomes, lipid microvesicular bodies which transports various cellular components including miRNA, from BALF of asthmatics showed significant difference in the levels of Let-7 miRNA. [45] Taken together, these results suggest an anti-inflammatory role of Let-7 miRNA in asthma and other inflammatory diseases. | Figure 3: Exogenous delivery of Let-7 miRNA inhibits IL-13 and attenuates asthma features. IL-13 is a central mediator of allergic asthma and is posttranscriptionally regulated by Let-7 miRNA family. Inhaled allergen is taken up by antigen presenting cells (APC) in the lung and activates Th-2 cells. Activated Th-2 cells have low levels of Let-7 miRNA and high levels of IL-13. Exogenous administration of Let-7 miRNA in allergically inflamed lungs down regulates IL-13 and attenuates allergic phenotype such as inflammation, mucus secretion, subepithelial fibrosis, and AHR
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| Future Perspective | | |
With the advancement of sequencing coupled with proteomics techniques, such as Per cross-linking and immunoprecipitation (PerCLIP) and stable isotope labeling in cell culture (SILAC), hundreds of new miRNA-mRNA pairs have been identified; however, the major challenge remains to establish the role of these miRNAs in clinical disease and to identify the regulatory mechanisms or pathways related to miRNA expression. In vivo validation of miRNA function in clinically-relevant animal models is useful and facilitates the Phase 2 clinical trials. Also, the development of miRNAs transgenic mice will greatly facilitate research in this exciting area. There is also much commercial interest in the development of miRNA based therapy for different disease which primarily focused towards developing technologies to either block or enhance miRNA expression in vivo as a tool to the management of human disease.
Despite considerable progress in understanding the role of miRNA in development of complex disorder like asthma, two significant challenges remains a barrier to convert experimental knowledge to the next stage where they can be clinically implemented.
The first important challenge is to develop stable miRNA mimics or inhibitors with a minimum side effect. This is important, since RNA is prone to degrade rapidly by endogenous enzymes. Chemical modifications such as cholesterol and lock nucleic acid (LNA) were utilized to impart stability in miRNA inhibitors and have enabled efficient delivery in in vivo conditions. [46],[47] Similar modification in miRNA mimics could potentially affect its functions. Other alternatives are lentiviral or adenoviral based over expression vectors of these miRNA mimics which need to be carefully evaluated in the future.
A second obstacle is the efficient cell specific delivery of stable miRNA mimics or inhibitors. This will not only helpful in cutting cost, but also reduce undesirable side effects. Recently, nanoparticle-based delivery methods were employed to deliver them in specific cell types, but most of them are under clinical trials. [48]
Despite these challenges for potential use of miRNAs as a therapy, the use of miRNAs holds great promise as a new treatment since these molecules are regulators of physiological processes and often dysregulated under disease conditions. More recently, miravirsen, an inhibitor of miR-122 was used in Phase 3 clinical trials in the patients with chronic hepatitis C virus (HCV), showed promising results without evidence of viral resistance. [49] Other miRNAs currently in preclinical trials are miR-208, miR-499, and miR-195 for the treatment of cardiovascular disease; and miR-34 and Let-7 for developing cancer therapeutics. [50],[51],[52] Future of miRNA-based therapy in case of pulmonary disorders, such as asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) seems to be promising as indicated by animal studies. Also, as delivery of miRNA mimics or inhibitors in the lungs is comparatively easier, it offers better opportunity for developing therapeutics with minimal side effects.
| Acknowledgment | | |
The author thanks Mr. Manish Kumar, CSIR-Institute of Genomics and Integrative Biology (IGIB) for helping him in preparing the manuscript.
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