Open access peer-reviewed chapter

Pathogenic Roles of MicroRNA in the Development of Asthma

Written By

Xiaoyan Dong and Nanbert Zhong

Submitted: November 3rd, 2018 Reviewed: March 18th, 2019 Published: April 11th, 2019

DOI: 10.5772/intechopen.85922

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Abstract

Asthma is a common and chronic inflammatory disease. Pathogenic mechanism underlying asthma is complicated. The inflammatory reactions in asthma have been recognized to involve mast cells, eosinophils, lymphocytes (T cells, B cells), macrophages, and dendritic cells. MicroRNA (miRNA, miR) is a group of small noncoding RNAs with 21–25 nucleotides (nt) in length, which impact biologic responses through the regulation of mRNA transcription and/or translation. MicroRNAs are related to developmental processes of many immunologic diseases. Most studies showed that regulation of miRNAs to their targeting genes appears to play an important role in the development of asthma. This chapter has discussed altered expression of miRNAs in cells and tissues from patients with asthma, in order to better understand the mechanics of pathogenesis of asthma. In addition, the regulation of miRNAs as a novel therapeutic approach will require a deeper understanding of their function and mechanism of action.

Keywords

  • microRNA asthma
  • inflammation reaction

1. Introduction

Pediatric asthma is a global problem. In the last decade, its incidence has highly increased, particular growing by 10% in China [1]. Etiologically, asthma attack, due to gene-environmental interactions, can also be induced by allergy factors, including air pollution, pollen, fungi and dust mites, food, and so on [2]. As a chronic inflammatory disease and a polygenic hereditary disease, the mechanism of asthma is not clearly understood until now. The adaptive and innate immune system with the involvement of mast cells, eosinophils, lymphocytes (T cells, B cells), macrophages, and dendritic cells, even epithelial cells and structure cells, contributed to the inflammation reaction of asthma [3, 4, 5]. Moreover, change in the secretion of IgE and cytokines, including gamma-interferon (γ-IFN) and tumor necrosis factor (TNF-α), is important in asthma attacks [6, 7, 8]. As an immune regulator, microRNA (miRNA or miR) regulates on target gene mRNA and plays an important role in the development and pathogenesis of asthma.

MicroRNAs are a group of small nonprotein-coding RNAs that are 21–25 nucleotides in length. They act as transcriptional regulators involved in many complex human disorders and in biological processes including cell proliferation and apoptosis [9, 10]. Childhood asthma susceptibility is associated with mutations in specific gene mRNA and/or their specific miRNA. For example, HLA-G has been identified as an asthma susceptibility gene [11], which was found to be the target gene of miR-148a, miR-148b, and miR-152. Further support for the theory that miRNA changes may be the cause of childhood asthma. The specific genotype of children with asthma was related to the significant difference in allele polymorphism (SNP) of rs2910164G/C and rs2292832C/T of pre-miRNA [12]. It showed that miR-223 was involved in the maturation and function of neutrophil differentiation [13]. miR-27b-3p, miR-513a-5p, and miR-22-3p were also indicated to have influenced dust mite-induced asthma by regulating its target gene [14, 15]. In a murine model of acute and chronic asthma study, abnormal expression of miRNAs including miR-146b, miR-223, miR-29b, miR-29c, miR-483, miR-5745p, miR-672, and miR-690 in asthma was detected [16]. It was found that miRNA plays an important role in regulating immune pathway(s). A lot of studies have focused on the relationship between miRNA and asthma during decades, which involved not only in inflammation cells and cytokines but also in the treatment of glucocorticoids (Table 1). In this chapter, we discuss the relationship of miRNAs to their targeted mRNA(s) involved in the inflammation cell in asthma, in order to review the pathogenic mechanism of asthma.

miRNAInflammatory responseReaction and cell differentiateReference
miRNA-223Immune inflammatory responseNeutrophils mature and differentiate[13]
miRNA-146, miRNA-146aAsthma, innate immune responsesAirway epithelium, NF-kappaB pathway[17, 18]
miRNA-147Immune inflammatory responseTLR signaling pathway[19]
miRNA-145AsthmaComparable to glucocorticoid treatment[20]
miRNA-155Immune inflammatory response, asthmaTLR signaling pathway, regulation of allergic inflammation, macrophage inflammatory response, Th2 priming of dendritic cells[21, 22, 23, 24]
miRNA-21Immune inflammatory response, asthmaTLR signaling pathway, NF-kB, IL-12p35 polarization[25, 26, 27]
miRNA-124Allergy inflammationM2 phenotype of monocytic cells[28]
miRNA-148a, miR-148b, and miR-152AsthmaHLA-G[11, 29]
miRNA-126AsthmaTh2 response, airway hyperresponse[30]
let-7AsthmaIl-13, regulation of allergic inflammation[31, 32, 33]
miRNA-221AsthmaMast cell activity regulates the production of cytokines[34, 35]
miRNA-9AsthmaRegulates steroid-resistant airway hyperresponsiveness[36]
miRNA-672, miRNA-143AsthmaExpression of metalloproteinase[37]
miR-19aAsthmaEnhances proliferation of bronchial epithelial cells by targeting TGFbetaR2 gene[38]
miRNA-203AsthmaNegatively regulates c-Abl, ERK1/2 phosphorylation, and proliferation in smooth muscle cells[39]
miRNA-133, miR-133aAsthmaUpregulation of Rhoa in bronchial smooth muscle cells[40]
miR-192AsthmaDecreased expression in peripheral blood of asthmatic individuals undergoing an allergen inhalation challenge[41]

Table 1.

The relationship of miRNA and inflammation response.

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2. miRNA in T cell and B cell

T cell and B cell play an important role in immune mechanism, especially innate and adaptive immunity, of asthma. As an immune regulator, miRNA influences on these two cells and regulates their proliferation and function. Many studies have been focused on the regulation of miRNA to T cell and B cell in order to clear the mechanism of asthma.

2.1 T cell, follicular helper T cells (TFH cells), and Th17

T follicular helper (Tfh) cells are essential for the formation of germinal centers (GCs). As a subset of CD4+, it mediates GC formation and maintenance and provides help to antigen-specific B cells during infection and vaccination. Th17 cells have also been implicated in the pathogenesis of several autoimmune and inflammatory diseases [42, 43, 44]. Th17 cells also mediate immune responses that are involved in maintaining epithelial barrier integrity, and it has been widely suggested that some cases of asthma may be caused by dysregulated Th17 responses [44, 45]. MiRNA also regulates the differentiation and function of these cells.

It was found that the miR-17-92 cluster’s increasing role in regulating the immune system is involved in innate and adaptive immunity, including B cells and subsets of T cells such as Th1, Th2, T follicular helper cells, regulatory T cells, monocytes/macrophages, NK cells, and dendritic cells [46]. Moreover, the study found that the miR-17 approximately 92 cluster is a critical regulator of T cell-dependent antibody responses and follicular helper T cells’ (TFH cells) differentiation [47].

We knew that the relationship of miRNA and its target gene mRNA is not a one-to-one correspondence. Target gene mRNA could be regulated by many miRNAs, or one miRNA could regulate a number of mRNAs. A study showed that some miRNAs with strong probability may induce miR-27b, miR-27a, miR-30c, miR-1, and miR-141 or inhibit miR-20b, miR-93, miR-20a, miR-152, miR-21, and miR-106a in Th17 differentiation by targeting negative or positive regulators of Th17 differentiation, respectively [48]. In a regulatory network model of murine T helper cell differentiation, the miR-212~132 and miR-182~183 clusters were significantly upregulated, and the overall miR-106~363 cluster was downregulated, which predicted to affect Th17 cell differentiation. In vitro, when miR-18b, miR-106a, and miR-363-3p were transfected into primary murine Cd4(+) lymphocytes, the expression of retinoid-related orphan receptor c (Rorc), Rora, IL17a, and IL17f and abolished secretion of Th17-mediated interleukin-17a (IL17a) have declined [49].

In addition, miR-18a directly targeted Smad4, Hif1a, and Rora in the Th17 cell gene expression program. All of these reveal that activating signals influence the outcome of Th cell differentiation via differential regulation of mature microRNAs within a common cluster [50]. miR-18a was the most dynamically upregulated microRNA of the miR-17-92 cluster during Th17 cell differentiation. Based on which, the involvement of miR-18a in the regulation of T-cell differentiation was demonstrated.

miR-155, as an important regulator in asthma, was involved in many pathways in allergy disease in Table 1. It was shown that the function in macrophage inflammatory response [23] is differentially expressed in allergic T cells exposed to DM extract compared to in nonallergic cells. The level of miR-155 expression was positively associated with the expression of the TH2 cytokines IL-5 and IL-13. When miR-155 was inhibited by glucocorticoids in Jurkat T cells, then the production of these cytokines were inhibited [51].

Several differentially expressed miRNAs in asthma, such as miRNA-34/449, let-7, miRNA-19, miRNA-21, and miRNA-455, were identified in various cell types and tissues including epithelial cells, T cells, type 2 innate lymphoid cells, lung tissues, and smooth muscles. These miRNAs are involved in epithelial differentiation, mucus production, airway remodeling, and inflammation as well [52]. miR-146a has been shown to modulate T-cell immunity as well as enhance class switch and secretion of IgE in B cells by upregulating 14-3-3 sigma expression [53].

2.2 miRNA regulates B cell

B cells play a critical role in immune responses, but the regulation of microRNAs to B-cell proliferation and function was partially understood. Not only miR-17-92 cluster was involved in B cell [46], but miR-146a also enhances class switch and secretion of IgE in B cells [53]. As an important immune regulatory cell, thrombospondin 1 (TSP1)-producing B cells were regulated by miRNAs as well. miR-98 can suppress the expression of TSP1 in the peripheral B cells of patients with allergic asthma [54]. Further study revealed that overexpression of miR-29b in human B cells precipitated a reduction in overall AID protein whose activity affected the function of class-switch recombination (CSR) and then results in corresponding diminution in CSR to IgE [55].

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3. miRNA and mast cell

It is essential that mast cells have major effector and immune regulatory functions in IgE-associated allergic diseases or in innate and adaptive immune responses. But their mechanism was not clear yet. miRNAs provide an additional layer in the regulation of gene expression acting as repressors with several targets at the posttranscriptional level. Several studies showed that miRNA expression patterns during differentiation and activation of mast cells. The expression of many miRNAs changes following IgE-FcepsilonRI cross-linking in activated mast cells. Upregulated expression of miR-221 promotes IgE-mediated activation of mast cell degranulation by PI3K/Akt/PLCgamma/Ca2+ signaling pathway, in a non-NF-kappaB-dependent manner [56]. Downregulation of miR-223 promotes degranulation viathe PI3K/Akt pathway by targeting IGF-1R in mast cells [57]. In cockroach allergen model of asthma, when miRNA-33b was overexpressed, mast cell degranulation was inhibited through suppression of the calcium release and IgE-FcepsilonRI pathway [58]. In line with this, neutralization of miR-132 by anti-miR inhibitor leads to sustained production of HB-EGF protein in activated mast cells [59].

Cytokine is also related to miRNA and mast cells in inflammation response of asthma. The treatment of IL-10 has been shown to suppress TNF production in mast cells. IL-10 effects are dependent on Stat3 activation, eliciting miR-155 expression, with a resulting loss of suppressor of cytokine signaling-1 [60]. miR-221, which was overexpressed in a murine asthma model, stimulated IL-4 secretion in mast cells through a pathway involving PTEN, p38, and NF-kappaB [61]. miR-223 reduces IL-6 secretion in mast cells by inhibiting the IGF1R/PI3K signaling pathway [62]. Mex-3B, an antisense oligonucleotide targeting, directly upregulates IL-33 expression by inhibiting miR-487b-3p-mediated repression of IL-33 [63].

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4. miRNA and dendritic cells

Dendritic cells (DCs) are the professional antigen-presenting cells (APCs) in the lung. They are found to be crucial in the induction and maintenance of allergic asthma by cross-linking innate and adaptive immune responses. After transfection with miR-23b reagents, DCs were evaluated for endocytic ability, surface marker expression, cytokine secretion, and CD4+ T-cell differentiation. The study proved that miR-23b is capable of inducing tolerogenic DC activity and Treg responses in vitro through the inhibition of the Notch1 and NF-kappaB signaling pathways; thus, miR-23b might represent a therapeutic target for the management of allergic diseases [64].

miR-155 has been shown to be a crucial regulator of the immune system mentioned above. Not only miR-155 can influence on T cell function but also regulate the activity of DCs. Deficiency of miR-155 on DCs was also associated with impaired purinergic receptor signaling and alleviates AAI by diminishing Th2 priming capacity and ATP-/P2R-induced activation of DCs in mice [24].

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5. miRNA and inflammatory phenotype (neutrophilic asthma and eosinophilic asthma)

Asthma may be classified according to severity and inflammatory phenotype and is likely to be distinguished by specific microRNA (miRNA) expression profiles. The study of miRNA expression in sputum supernatants with the inflammatory cells in severe asthma was taken out. Expression of miR-629-3p, miR-223-3p, and miR-142-3p was significantly upregulated in the sputum of patients with severe asthma compared with that in healthy control subjects and was highest in patients with neutrophilic asthma. It suggested that these miRNAs are related to asthma inflammatory phenotype [65].

Single-nucleotide polymorphisms (SNPs) in miRNAs could affect their efficiency in binding to messenger RNAs (mRNAs), which was taken little into account before. In a study in Korean population, it showed that the CT/CC genotype of miR-196a2 at locus rs11614913 was associated with eosinophilic asthma and a higher sputum eosinophil count than the TT genotype. The CG/GG genotype at rs2910164 of miR-146a had a hyperresponsiveness in airway compared with the CC genotype. The AG/GG genotype at rs3746444 of miR-499 manifested higher predicted values of forced expiratory volume in 1 s (%FEV1) than the AA genotype [66].

A study about evaluating clinical potential of plasma miR-21 and miR-146a involved in T helper cell differentiation in childhood asthma found that the levels of miR-21 and miR-146a were not only positively correlated with eosinophil percentage but also associated with FEV1. miR-21 and miR-146a are upregulated in asthmatic children. miR-21 and miR-146a play a role in eosinophilic endotypic classification of asthma [67]. Moreover, its data show that miR-185-5p profile in eosinophils can be used as asthma diagnosis biomarker in serum and that this profile is able to rank asthma severity [68].

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6. miRNA and macrophage

Monocytes and macrophages are important roles of the immune system, which possess pleiotropic effector and immunoregulatory functions. Classical activation (M1) and alternative activation (M2) of macrophages are necessary in the function. M1 polarization of macrophages results in the production of proinflammatory cytokines and antimicrobial and tumoricidal activity, whereas M2 polarization of macrophages is related to immunosuppression, tumorigenesis, wound repair, and elimination of parasites [69]. It also reveals that miRNAs were involved in M macrophages’ activity. miR-511 is increased in macrophages following IL-4 and IL-13 stimulation and decreased in M1 macrophages both in vitro and in vivo [70]. Particularly, miR-9, miR-127, miR-155, and miR-125b have been shown to promote M1 polarization, while miR-124, miR-223, miR-34a, let-7c, miR-132, miR-146a, and miR-125a-5p may induce M2 polarization in macrophages by targeting various transcription factors and adaptor proteins. Differentiation of monocytes to macrophages is inhibited by miR-24, miR-30b, miR-142-3p, and miR-199a-5p. MiR-155 and miR-142-3p inhibit macrophage proliferation, compared to let-7a. Interestingly, miR-155 has both pro- and antiapoptotic roles, whereas miR-21 and let-7e negatively regulate macrophage apoptosis [69, 71, 72]. These data revealed that the function of miRNAs in modulating macrophage polarization may have potential way in the treatment of inflammation-related diseases.

On the other hand, studying the development of allergy disease in maternal pregnancy revealed that the embryonic development is highly sensitive to xenobiotic toxicity. If exposed to environmental toxins in utero, it affects physiological responses of the progeny. In the animal model, there was a lower expression of miR-130a and increased expression of miR-16 and miR-221 in the lungs of mice which were exposed to sidestream cigarette smoke (SS) or secondhand smoke exhibit. These miRNAs regulate HIF-1 alpha-regulated apoptotic, angiogenic, and immune pathways. This process will lead to increase incidence of allergic asthma (AA) and bronchopulmonary dysplasia (BPD) in the progenies [73].

Besides, the expression of miRNAs was different in fungal bioaerosols which are ubiquitous in the environment, and human exposure can result in a variety of health effects ranging from systemic, subcutaneous, and cutaneous infections to respiratory morbidity including allergy, asthma, and hypersensitivity pneumonitis. It was found that miRNAs were involved in the inflammatory stimuli exposure to fungal. In studies of exposures to fungi (such as Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans), it was revealed that several miRNAs that were shared between responses to these species including miR-125 a/miR-125 b, miR-132 [43], miR-146a, and miR-29a/miR-29b were also involved in macrophage polarization/activation, TLR-mediated signaling, natural killer cell function, C-leptin signaling, and inhibition of Th1 immune response, respectively [74]. On the other hand, miR-487b can suppress the levels of mRNA and protein for IL-33, which plays an important role in macrophage activation for innate host defense and proinflammatory responses during the differentiation of bone marrow-derived macrophages (BMDMs) [75].

In summary, miRNAs exert their effect by binding to complementary nucleotide sequences of the targeted messenger RNA, thus forming an RNA-induced silencing complex. miRNAs play important roles in many aspects of macrophage biology and thereby affect many biological and pathological conditions, like monocyte differentiation and development, macrophage polarization, infection, tumor growth, inflammatory activation, and so on [71, 72]. Numerous studies have demonstrated the important role of miRNA in the pathogenesis of childhood asthma, suggesting that miRNA plays a regulatory role between genes and the environment as well as allergic airway inflammation. The mechanism of miRNA activity involves a large number of miRNAs, which take mRNA with multiple functions as target genes and synergistically regulate multiple aspects of complex pathophysiological processes in childhood asthma. The role of miRNAs in inflammation cells is important in both innate and acquired immunity in which T cell, B cell, mast cells, macrophages, and dendritic cells are involved. The role of miRNAs in these cell types, miR-17-92 cluster, miR-221, miR-223, miR-146a, and miR-155, may be crucial (Figure 1). Depending on these roles of miRNAs in dendritic cells, mast cells, and macrophages, we speculate about possible future directions in the field [76]. It is likely variant miRNAs form a network in which these miRNAs may interact with each other and alter the expression of target genes in the inflammation process of pediatric asthma. On the other hand, it is envisaged that targeted manipulation of specific miRNAs could be developed as a new treatment for asthma. At present, our group has already had some result about the relationship of miRNA to target gene in dust mite-induced asthma. Depending on this review, further investigation should be pursued on the immune regulatory function of miRNA in children’s asthma.

Figure 1.

miR-17-92 cluster, miR-221, miR-223, miR-146a, and miR-155 are associated with inflammation cells. (A) Downregulation of miR-223 promotes degranulationviathe PI3K/Akt pathway by targeting IGF-1R and reduces IL-6 secretion in mast cells. It also induced M2 polarization. (B) miR-221 promoted IgE-mediated activation of mast cells degranulation by PI3K/Akt/PLCgamma/Ca2+ signaling pathway and stimulated IL-4 secretion in mast cells through a pathway involving PTEN, p38, and NF-kappaB. (C) miR-17~92 cluster as a critical regulator of T-cell-dependent antibody responses and follicular helper T cell (TFH cell) and Th17 differentiation. It enhances class switch and secretion of IgE in B cells. (D) miR-146 modulated T-cell immunity and enhanced class switch and secretion of IgE in B cells. miR-146a played a role in eosinophilic endotypic classification of asthma. It induced M2 polarization as well. (E) miR-155 was associated with Th2 cell and cytokine secretion. Deficiency of miR-155 on DCs was also related to impaired purinergic receptor signaling and alleviates AAI by diminishing Th2 priming capacity and ATP-/P2R-induced activation of DCs. It promoted M1 polarization.

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Acknowledgments

This study was supported by Shanghai Science and Science Commission International Cooperation Project (No. 18410721300) and Project on the cross project of Shanghai Jiaotong University (YG2017MS34).

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Conflict of interest

There was no conflict of interest (economic, personal, scientific, healthcare, educational, religious, and social) interfering with the chapter.

References

  1. 1. The National Cooperative Group on Childhood Asthma, Institute of Environmental Health and Related Product Safety, Chinese Center for Disease Control and Prevention. Third nation wide survey of childhood asthma in urban areas of China. Chinese Journal of Pediatrics. 2013;51:729-740
  2. 2. Rottier BL, Eber E, Hedlin G, Turner S, Wooler E, Mantzourani E, et al. Monitoring asthma in childhood: Management-related issues. European Respiratory Review. 2015;24:194-203
  3. 3. Snijders D, Agostini S, Bertuola F, Panizzolo C, Baraldo S, Turato G, et al. Markers of eosinophilic and neutrophilic inflammation in bronchoalveolar lavage of asthmatic and atopic children. Allergy. 2010;65:978-985
  4. 4. Larose MC, Chakir J, Archambault AS, Joubert P, Provost V, Laviolette M, et al. Correlation between CCL26 production by human bronchial epithelial cells and airway eosinophils: Involvement in patients with severe eosinophilic asthma. The Journal of Allergy and Clinical Immunology. Oct 2015;136(4):904-913
  5. 5. Roth M, Zhao F, Zhong J, Lardinois D, Tamm M. Serum IgE induced airway smooth muscle cell remodeling is independent of allergens and is prevented by omalizumab. PLoS One. 2015;10:e0136549
  6. 6. Chang YJ, DeKruyff RH, Umetsu DT. The role of type 2 innate lymphoid cells in asthma. Journal of Leukocyte Biology. 2013;94:933-940
  7. 7. Sumino K, Tucker J, Shahab M, Jaffee KF, Visness CM, Gern JE, et al. Antiviral IFN-gamma responses of monocytes at birth predict respiratory tract illness in the first year of life. The Journal of Allergy and Clinical Immunology. 2012;129(1267-1273):e1261
  8. 8. Choi JP, Kim YS, Kim OY, Kim YM, Jeon SG, Roh TY, et al. TNF-alpha is a key mediator in the development of Th2 cell response to inhaled allergens induced by a viral PAMP double-stranded RNA. Allergy. 2012;67:1138-1148
  9. 9. Zhang B, Farwell MA. microRNAs: A new emerging class of players for disease diagnostics and gene therapy. Journal of Cellular and Molecular Medicine. 2008;12:3-21
  10. 10. Pauley KM, Cha S, Chan EK. MicroRNA in autoimmunity and autoimmune diseases. Journal of Autoimmunity. 2009;32:189-194
  11. 11. Tan Z, Randall G, Fan J, Camoretti-Mercado B, Brockman-Schneider R, Pan L, et al. Allele-specific targeting of microRNAs to HLA-G and risk of asthma. American Journal of Human Genetics. 2007;81:829-834
  12. 12. Su XW, Yang Y, Lv ML, Li LJ, Dong W, Miao L, et al. Association between single-nucleotide polymorphisms in pre-miRNAs and the risk of asthma in a Chinese population. DNA and Cell Biology. 2011;30:919-923
  13. 13. Johnnidis JB, Harris MH, Wheeler RT, Stehling-Sun S, Lam MH, Kirak O, et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature. 2008;451:1125-1129
  14. 14. Dong X, Xu M, Ren Z, Gu J, Lu M, Lu Q , et al. Regulation of CBL and ESR1 expression by microRNA-223p, 513a-5p and 625-5p may impact the pathogenesis of dust mite-induced pediatric asthma. International Journal of Molecular Medicine. 2016;38:446-456
  15. 15. Dong X, Zhong N, Fang Y, Cai Q , Lu M, Lu Q. MicroRNA 27b-3p modulates SYK in pediatric asthma induced by dust mites. Frontiers in Pediatrics. 22 Oct 2018;6:301. DOI: 10.3389/fped.2018.00301. eCollection 2018
  16. 16. Garbacki N, Di Valentin E, Huynh-Thu VA, Geurts P, Irrthum A, Crahay C, et al. MicroRNAs profiling in murine models of acute and chronic asthma: A relationship with mRNAs targets. PLoS One. 2011;6:e16509
  17. 17. Liu X, Nelson A, Wang X, Kanaji N, Kim M, Sato T, et al. MicroRNA-146a modulates human bronchial epithelial cell survival in response to the cytokine-induced apoptosis. Biochemical and Biophysical Research Communications. 2009;380:177-182
  18. 18. Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:12481-12486
  19. 19. Liu G, Friggeri A, Yang Y, Park YJ, Tsuruta Y, Abraham E. miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophage inflammatory responses. Proceedings of the National Academy of Sciences of the United States of America. 2009;106:15819-15824
  20. 20. Collison A, Mattes J, Plank M, Foster PS. Inhibition of house dust mite-induced allergic airways disease by antagonism of microRNA-145 is comparable to glucocorticoid treatment. The Journal of Allergy and Clinical Immunology. 2011;128(160-167):e164
  21. 21. Tang B, Xiao B, Liu Z, Li N, Zhu ED, Li BS, et al. Identification of MyD88 as a novel target of miR-155, involved in negative regulation ofHelicobacter pylori-induced inflammation. FEBS Letters. 2010;584:1481-1486
  22. 22. Zhang YY, Zhong M, Zhang MY, Lv K. Expression and clinical significance of miR-155 in peripheral blood CD4(+);T cells of patients with allergic asthma. Chinese Journal of Cellular and Molecular Immunology. 2012;28:540-543
  23. 23. O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proceedings of the National Academy of Sciences of the United States of America. 2007;104:1604-1609
  24. 24. Zech A, Ayata CK, Pankratz F, Meyer A, Baudiss K, Cicko S, et al. MicroRNA-155 modulates P2R signaling and Th2 priming of dendritic cells during allergic airway inflammation in mice. Allergy. 2015;70:1121-1129
  25. 25. Lu TX, Munitz A, Rothenberg ME. MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression. Journal of Immunology. 2009;182:4994-5002
  26. 26. Sheedy FJ, Palsson-McDermott E, Hennessy EJ, Martin C, O'Leary JJ, Ruan Q , et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nature Immunology. 2010;11:141-147
  27. 27. Sawant DV, Yao W, Wright Z, Sawyers C, Tepper RS, Gupta SK, et al. Serum microRNA-21 as a biomarker for allergic inflammatory disease in children. MicroRNA. 2015;4:36-40
  28. 28. Veremeyko T, Siddiqui S, Sotnikov I, Yung A, Ponomarev ED. IL-4/IL-13-dependent and independent expression of miR-124 and its contribution to M2 phenotype of monocytic cells in normal conditions and during allergic inflammation. PLoS One. 2013;8:e81774
  29. 29. Nicodemus-Johnson J, Laxman B, Stern RK, Sudi J, Tierney CN, Norwick L, et al. Maternal asthma and microRNA regulation of soluble HLA-G in the airway. The Journal of Allergy and Clinical Immunology. 2013;131:1496-1503
  30. 30. Mattes J, Collison A, Plank M, Phipps S, Foster PS. Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease. Proceedings of the National Academy of Sciences of the United States of America. 2009;106:18704-18709
  31. 31. Kumar M, Mabalirajan U, Agrawal A, Ghosh B. Proinflammatory role of let-7 miRNAs in experimental asthma? The Journal of Biological Chemistry. 2010;285(le19) author reply le20
  32. 32. Polikepahad S, Knight JM, Naghavi AO, Oplt T, Creighton CJ, Shaw C, et al. Proinflammatory role for let-7 microRNAS in experimental asthma. The Journal of Biological Chemistry. 2010;285:30139-30149
  33. 33. Kumar M, Ahmad T, Sharma A, Mabalirajan U, Kulshreshtha A, Agrawal A, et al. Let-7 microRNA-mediated regulation of IL-13 and allergic airway inflammation. The Journal of Allergy and Clinical Immunology. 2011;128:1077-1085.e1071-1010
  34. 34. Mayoral RJ, Deho L, Rusca N, Bartonicek N, Saini HK, Enright AJ, et al. MiR-221 influences effector functions and actin cytoskeleton in mast cells. PLoS One. 2011;6:e26133
  35. 35. Mayoral RJ, Pipkin ME, Pachkov M, van Nimwegen E, Rao A, Monticelli S. MicroRNA-221-222 regulate the cell cycle in mast cells. Journal of Immunology. 2009;182:433-445
  36. 36. Li JJ, Tay HL, Maltby S, Xiang Y, Eyers F, Hatchwell L, et al. MicroRNA-9 regulates steroid-resistant airway hyperresponsiveness by reducing protein phosphatase 2A activity. The Journal of Allergy and Clinical Immunology. 2015;136:462-473
  37. 37. Di Valentin E, Crahay C, Garbacki N, Hennuy B, Gueders M, Noel A, et al. New asthma biomarkers: Lessons from murine models of acute and chronic asthma. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2009;296:L185-L197
  38. 38. Haj-Salem I, Fakhfakh R, Berube JC, Jacques E, Plante S, Simard MJ, et al. MicroRNA-19a enhances proliferation of bronchial epithelial cells by targeting TGFbetaR2 gene in severe asthma. Allergy. 2015;70:212-219
  39. 39. Liao G, Panettieri RA, Tang DD. MicroRNA-203 negatively regulates c-Abl, ERK1/2 phosphorylation, and proliferation in smooth muscle cells. Physiological Reports. 2015;3
  40. 40. Chiba Y, Tanabe M, Goto K, Sakai H, Misawa M. Down-regulation of miR-133a contributes to up-regulation of Rhoa in bronchial smooth muscle cells. American Journal of Respiratory and Critical Care Medicine. 2009;180:713-719
  41. 41. Yamamoto M, Singh A, Ruan J, Gauvreau GM, O'Byrne PM, Carlsten CR, et al. Decreased miR-192 expression in peripheral blood of asthmatic individuals undergoing an allergen inhalation challenge. BMC Genomics. 2012;13:655
  42. 42. Gaffen SL, Jain R, Garg AV, Cua DJ. The IL-23-IL-17 immune axis: From mechanisms to therapeutic testing. Nature Reviews Immunology. 2014;14:585-600
  43. 43. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annual Review of Immunology. 2009;27:485-517
  44. 44. Weaver CT, Elson CO, Fouser LA, Kolls JK. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annual Review of Pathology. 2013;8:477-512
  45. 45. Pappu R, Rutz S, Ouyang W. Regulation of epithelial immunity by IL-17 family cytokines. Trends in Immunology. 2012;33:343-349
  46. 46. Kuo G, Wu CY, Yang HY. MiR-17-92 cluster and immunity. Journal of the Formosan Medical Association. 2019;118:2-6
  47. 47. Baumjohann D, Kageyama R, Clingan JM, Morar MM, Patel S, de Kouchkovsky D, et al. The microRNA cluster miR-17 approximately 92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nature Immunology. 2013;14:840-848
  48. 48. Honardoost MA, Naghavian R, Ahmadinejad F, Hosseini A, Ghaedi K. Integrative computational mRNA-miRNA interaction analyses of the autoimmune-deregulated miRNAs and well-known Th17 differentiation regulators: An attempt to discover new potential miRNAs involved in Th17 differentiation. Gene. 2015;572:153-162
  49. 49. Kastle M, Bartel S, Geillinger-Kastle K, Irmler M, Beckers J, Ryffel B, et al. microRNA cluster 106a~363 is involved in T helper 17 cell differentiation. Immunology. 2017;152:402-413
  50. 50. Montoya MM, Maul J, Singh PB, Pua HH, Dahlstrom F, Wu N, et al. A distinct inhibitory function for miR-18a in Th17 cell differentiation. Journal of Immunology. 2017;199:559-569
  51. 51. Daniel E, Roff A, Hsu MH, Panganiban R, Lambert K, Ishmael F. Effects of allergic stimulation and glucocorticoids on miR-155 in CD4(+) T-cells. American Journal of Clinical and Experimental Immunology. 2018;7:57-66
  52. 52. van den Berge M, Tasena H. Role of microRNAs and exosomes in asthma. Current Opinion in Pulmonary Medicine. 2019;25:87-93
  53. 53. Li F, Huang Y, Huang YY, Kuang YS, Wei YJ, Xiang L, et al. MicroRNA-146a promotes IgE class switch in B cells via upregulating 14-3-3sigma expression. Molecular Immunology. 2017;92:180-189
  54. 54. Chen L, Xu J, Chu X, Ju C. MicroRNA-98 interferes with thrombospondin 1 expression in peripheral B cells of patients with asthma. Bioscience Reports. 2017;37
  55. 55. Recaldin T, Hobson PS, Mann EH, Ramadani F, Cousins DJ, Lavender P, et al. miR-29b directly targets activation-induced cytidine deaminase in human B cells and can limit its inappropriate expression in naive B cells. Molecular Immunology. 2018;101:419-428
  56. 56. Xu H, Gu LN, Yang QY, Zhao DY, Liu F. MiR-221 promotes IgE-mediated activation of mast cells degranulation by PI3K/Akt/PLCgamma/Ca2+ pathway. Journal of Bioenergetics and Biomembranes. 2016;48:293-299
  57. 57. Wang Q , Zhao DY, Xu H, Zhou H, Yang QY, Liu F, et al. Down-regulation of microRNA-223 promotes degranulation via the PI3K/Akt pathway by targeting IGF-1R in mast cells. PLoS One. 2015;10:e0123575
  58. 58. Niu R, Xiao X, Liu B, Li Y, Zhong Y, Ma L. Inhibition of airway inflammation in a cockroach allergen model of asthma by agonists of miRNA-33b. Scientific Reports. 2017;7:7409
  59. 59. Molnar V, Ersek B, Wiener Z, Tombol Z, Szabo PM, Igaz P, et al. MicroRNA-132 targets HB-EGF upon IgE-mediated activation in murine and human mast cells. Cellular and Molecular Life Sciences. 2012;69:793-808
  60. 60. Qayum AA, Paranjape A, Abebayehu D, Kolawole EM, Haque TT, McLeod JJ, et al. IL-10-induced miR-155 targets SOCS1 to enhance IgE-mediated mast cell function. Journal of Immunology. 2016;196:4457-4467
  61. 61. Zhou Y, Yang Q , Xu H, Zhang J, Deng H, Gao H, et al. miRNA-221-3p enhances the secretion of interleukin-4 in mast cells through the phosphatase and tensin homolog/p38/nuclear factor-kappaB pathway. PLoS One. 2016;11:e0148821
  62. 62. Yang Q , Xu H, Yang J, Zhou Y, Zhao D, Liu F. MicroRNA-223 affects IL-6 secretion in mast cells via the IGF1R/PI3K signaling pathway. International Journal of Molecular Medicine. 2016;38:507-512
  63. 63. Yamazumi Y, Sasaki O, Imamura M, Oda T, Ohno Y, Shiozaki-Sato Y, et al. The RNA binding protein Mex-3B is required for IL-33 induction in the development of allergic airway inflammation. Cell Reports. 2016;16:2456-2471
  64. 64. Zheng J, Jiang HY, Li J, Tang HC, Zhang XM, Wang XR, et al. MicroRNA-23b promotes tolerogenic properties of dendritic cells in vitro through inhibiting Notch1/NF-kappaB signalling pathways. Allergy. 2012;67:362-370
  65. 65. Maes T, Cobos FA, Schleich F, Sorbello V, Henket M, De Preter K, et al. Asthma inflammatory phenotypes show differential microRNA expression in sputum. The Journal of Allergy and Clinical Immunology. 2016;137:1433-1446
  66. 66. Trinh HKT, Pham DL, Kim SC, Kim RY, Park HS, Kim SH. Association of the miR-196a2, miR-146a, and miR-499 polymorphisms with asthma phenotypes in a Korean population. Molecular Diagnosis & Therapy. 2017;21:547-554
  67. 67. Hammad Mahmoud Hammad R, Hamed D, Eldosoky M, Ahmad A, Osman HM, Abd Elgalil HM, et al. Plasma microRNA-21, microRNA-146a and IL-13 expression in asthmatic children. Innate Immunity. 2018;24:171-179
  68. 68. Rodrigo-Munoz JM, Canas JA, Sastre B, Rego N, Greif G, Rial M, et al. Asthma diagnosis using integrated analysis of eosinophil microRNAs. Allergy. Mar 2018;74(3):507-517
  69. 69. Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. Journal of Cellular Physiology. 2018;233:6425-6440
  70. 70. Karo-Atar D, Itan M, Pasmanik-Chor M, Munitz A. MicroRNA profiling reveals opposing expression patterns for miR-511 in alternatively and classically activated macrophages. The Journal of Asthma. 2015;52:545-553
  71. 71. Porta C, Riboldi E, Ippolito A, Sica A. Molecular and epigenetic basis of macrophage polarized activation. Seminars in Immunology. 2015;27:237-248
  72. 72. Weiss G, Schaible UE. Macrophage defense mechanisms against intracellular bacteria. Immunological Reviews. 2015;264:182-203
  73. 73. Singh SP, Chand HS, Langley RJ, Mishra N, Barrett T, Rudolph K, et al. Gestational exposure to sidestream (secondhand) cigarette smoke promotes transgenerational epigenetic transmission of exacerbated allergic asthma and bronchopulmonary dysplasia. Journal of Immunology. 2017;198:3815-3822
  74. 74. Croston TL, Lemons AR, Beezhold DH, Green BJ. MicroRNA regulation of host immune responses following fungal exposure. Frontiers in Immunology. 2018;9:170
  75. 75. Xiang Y, Eyers F, Herbert C, Tay HL, Foster PS, Yang M. MicroRNA-487b is a negative regulator of macrophage activation by targeting IL-33 production. Journal of Immunology. 2016;196:3421-3428
  76. 76. Montagner S, Orlandi EM, Merante S, Monticelli S. The role of miRNAs in mast cells and other innate immune cells. Immunological Reviews. 2013;253:12-24

Written By

Xiaoyan Dong and Nanbert Zhong

Submitted: November 3rd, 2018 Reviewed: March 18th, 2019 Published: April 11th, 2019