Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
To purchase hard copies of this book, please contact the representative in India:
CBS Publishers & Distributors Pvt. Ltd.
www.cbspd.com
|
customercare@cbspd.com
Asthma is a common chronic inflammatory disease. Pathogenic mechanism underlying asthma is complex. The inflammatory response of asthma includes lymphocytes (T, B cells), ILC2, eosinophils and other types of immune and inflammatory cells. T CD4+ T helper 2 cells (Th2 cells) are thought to play a central role in regulating the phenotype of allergic asthma. Asthma is often closely associated with Th1/Th2 cell imbalance. Non-coding RNAs (ncRNAs) are non-protein coding RNA molecules in the transcriptome, mainly including microRNAs (miRNAs), long non-coding RNAs and circRNAs, etc., which are widely found in eukaryotic transcriptome and participate in the regulation of a variety of biological processes. ncRNAs are considered to function as modulators of the immune system. Their biological changes represent an important mechanism for the development of immune-mediated diseases. This chapter mainly discusses the epigenetic regulation of Th2 cells and their cytokines in asthma by non-coding RNAs. It helps us to better understand the pathogenesis of asthma and find potential asthma biomarkers.
Department of Pulmonary, Shanghai Children’s Hospital, Shanghai Jiaotong University, China
Chao Wang
Department of Pulmonary, Shanghai Children’s Hospital, Shanghai Jiaotong University, China
Xiaoyan Dong*
Department of Pulmonary, Shanghai Children’s Hospital, Shanghai Jiaotong University, China
Nanbert Zhong*
New York State Institute for Basic Research in Developmental Disabilities, USA
*Address all correspondence to: dong_x_y0305@126.com and dongxy@shchildren.com.cn
1. Introduction
Asthma is a chronic airway inflammatory disease, associated with variable expiratory airflow limitation, clinically manifested as recurrent wheezing, shortness of breath, chest tightness, cough and other symptoms [1]. It has affected more than 300 million people worldwide and has become a major public health concern [2].
Non-coding RNAs (ncRNAs) are a class of non-coding RNA molecules widely found in eukaryotes and involved in a variety of biological regulatory processes. They have been extensively studied in human diseases [3, 4, 5]. NcRNAs mainly includes microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), etc.
The pathogenesis of asthma remains extremely complicated and the detailed mechanisms are not clarified. The most common phenotype is eosinophilic inflammation associated with Th2 response and concomitant atopic diseases. Asthma is often closely associated with Th1/Th2 cell imbalance. Th2 cells secrete Th2 cytokines, including interleukin-IL-4, IL-5, and IL-13, which amplify type 2 inflammation, while Th1 cells secrete Th1 cytokines [interferon IFN-γ, IL-2, lymphoid (LT)-α, and tumor necrosis factor TNF-α, which limit type 2 inflammation [6, 7]. The CD4+ T cells are major effector cells driving asthma-related inflammation and the skewing of T cells into Th2 cells can lead to imbalance of Th1-type and Th2-type cytokines, which promotes the onset and progression of asthma [8, 9]. Understanding the factors contributing to Th2 in asthma will provide important insights into the underlying pathogenesis of the disease. The skewing of T cells into Th2 cells causes an imbalance of Th1-type and Th2-type cytokines, which promotes the onset and progression of asthma. A number of studies have shown that ncRNAs may play an important role in Th2 cell-mediated inflammation in asthma. This chapter mainly discusses the epigenetic regulation of Th2 response in asthma by non-coding RNAs, in order to better understand the disease pathogenesis and find potential asthma biomarkers.
MicroRNAs are a group of small nonprotein-coding RNAs that are 18–25 nucleotides in length. They act as transcriptional regulators involved in many complex human disorders and in biological processes including cell proliferation and apoptosis [10, 11, 12]. MiRNA expression profiles have also been described in some allergic conditions and asthma [13]. Previous studies have suggested that miRNAs are involved in the development of allergic diseases by affecting Th1/Th2 polarization, promoting chronic inflammation and tissue remodeling of epithelial cells, and activating innate immune cells [13]. Th2-mediated inflammation is the core of the pathogenesis of allergic asthma. Th2-dominated T lymphocytes regulate allergic diseases by secreting a variety of proinflammatory cytokines. Recent studies have shown that most of the miRNAs involved increase Th2 cytokine secretion, reduce Th1 cytokine secretion, promote T cell differentiation to Th2, or play a role in the proliferation and hypertrophy of bronchial smooth muscle cells [14, 15, 16]. There is no doubt that miRNA plays a role in the regulation of asthma inflammation. MiRNAs may regulate Th2 in asthma by affecting Th1/Th2 balance, secretion of Th2 cytokines and related signaling pathways.
2.1 Regulation of Th2 cytokines by miRNAs
Th2-mediated inflammation is the core of the pathogenesis of allergic asthma. Typical cytokines involved in the Th2 response are IL-4, IL-5, and IL-13. Pua et al. [15] studied the miRNA related to Th2 cell differentiation and cytokine production by combining experimental and bioinformatics methods, and found that both miR-24 and miR-27 inhibited the production of IL-4 in T cells in vitro. Inhibition of the function of miR-145 suppresses house dust mites (HDM)-induced mucus hypersecretion in airway epithelial cells, eosinophilic inflammation, th2 cytokine production, and airway hyperresponsiveness as effectively as dexamethasone treatment. This study shows that miR-145 plays a key role in the occurrence and pathogenesis of allergic airway disease caused by house dust mites by inducing the release of IL-5 and IL-13 from Th2 cells [14]. Panganiban et al. found a variety of differentially expressed miRNAs in the serum of patients with asthma, and predicted that these miRNAs could regulate IL-5 and other TH2 mediators [17]. It was further confirmed that IL-5 was regulated by miRNA, and miR-1248 was identified as a positive regulator of IL-5 expression [17]. IL-10 levels are reduced in asthmatic patients, and the relative deficiency of IL-10 allows continued production of allergenic cytokines, such as IL-4 and IL-5, and other pro-inflammatory cytokines, including IL-1, TNF-α, and IL-6 [18]. Inhibition of miR-106a promotes IL-10 secretion and helps alleviate asthma symptoms by increasing Th2 response in a mouse model of asthma [19]. Simpson et al. demonstrated that the miR-17 ∼ 92 cluster, and specifically miR-19a, promotes Th2 cytokine production by simultaneously targeting inhibitors of the NF-κB, JAK–STAT, and PI (3)K pathways. Their data also suggest that upregulation of miR-19a in asthma airway T cells may be an indicator and cause of increased IL-13 production and may contribute to type 2 inflammation in asthma [20]. In ovalbumin (OVA)-induced asthma mice, miR-146a significantly inhibited inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF) and reduced levels of OVA-specific IgE and T-helper 2 cell type cytokines (IL-5 and IL-13) [21]. MiR-146a may act as a novel therapeutic molecule to modulate the immune response of asthma. MiR-155 has been shown to be a key modulator of the immune system. MiR-155 may regulate Th2 inflammation by regulating Th2 cell differentiation and the secretion of IL-4, IL-5 and IL-13. These studies suggest that targeting miR-155 may be a novel therapeutic strategy for human diseases induced by the Th2 immune response, such as asthma [22, 23]. It has been found that let-7 microRNAs inhibit IL-13 expression and thereby modulate Th 2 inflammation in an IL-13-dependent mouse model of allergic airway inflammation [24]. In ovalbumin (OVA) -induced asthma mice, intranasal administration of miR-410 significantly reduced the expression of IL-4 and IL-13 and effectively inhibited airway inflammation in OVA-induced asthmatic mice. Therefore, targeting to increase the expression of miR-410 may be a promising approach for the treatment of allergic asthma [25]. In a mouse model of asthma induced by ovalbumin, the researchers tested the airway hyperresponsiveness, rt-pcr detection of miR - 135 a content in the lung tissue of mice, HE staining to evaluate the pathological changes of lung tissue and ELISA and immunohistochemical detection of bronchoalveolar lavage fluid (BALF) and lung tissue of the tumor necrosis factor (TNF) - alpha, interleukin (IL) - 6, IL - 5 and eosinophils chemokine expression. The results of this study showed that miR-135a decreased expression in asthmatic mice, and miR-135a reduced the levels of inflammatory cytokines TNF-α, IL-6, IL-5 and eosinophilic chemokines in the lung tissue of mice, thereby reducing airway inflammation. Further research in this study showed that miR-135a inhibited airway inflammation in asthmatic mice by regulating the JAK/STAT signaling pathway [26]. Previous studies in human, animal models, and cell culture have shown that the Th2 cytokine IL-13 is an important cause of airway epithelial abnormalities in asthma [27, 28, 29]. Kuperman et al. used miRNA microarray to analyze the bronchial epithelial cells of asthmatic patients and healthy control subjects, and found that the expression of miR-34/449 family members was decreased in asthmatic patients. IL-13-induced reduction of miR-34/449 in bronchial epithelial cells may lead to changes in epithelial differentiation common in asthma [30]. Zhang et al. investigated the role of miR-221-3p in airway eosinophilic inflammation in a mouse model of HDM-induced allergic airway inflammation, and showed that epithelial miR-221-3p expression was reduced in asthma. Airway overexpression of miR-221-3p induced the expression of IL-4, IL-5, and IL-13 mRNAs in the lungs of mice induced by HDM [31]. The expression of miR-26a, miR-146a, and miR-31 and cytokine levels of IL-5, IL-8, IL-12, and TNF-α were measured in lung tissue and bronchoalveolar lavage fluid of asthmatic mice and children with ovalbumin induced asthma. The results showed that miR-26a, miR-146a, and miR-31 were significantly elevated in asthma, and were involved in the progression of asthma by regulating the expression of inflammatory cytokines IL-5, IL-8, IL-12, and TNF-α [32]. The systems immunology approach (the Impact of Differential Expression Across Layers, a network-based algorithm to prioritize disease-relevant miRs based on the central role of their targets in the molecular interactome) was used to antagonize miRs (miR27b, miR206, miR106b, miR203, and miR23b) in vitro, which has significantly reduced cytokine production in Th2 cells. These results suggest that these miRNAs play an important role in the Th2-driven immune response [33]. In conclusion, many miRNAs play an important role in asthma by regulating the secretion of Th2 cytokines. They may be new targets for the treatment of asthma in the future.
2.2 Regulation of Th1/Th2 balance by miRNAs
Qui et al. detected the levels of Th1- and Th2-related cytokines by ELISA, performed microRNA microarray assay and analyzed the differentiation marker gene of T helper cells by qRT-PCR. The results indicated that an imbalance of Th1/Th2 cells was present in the asthmatic patients; Runx3 expression is decreased in asthmatic patients; overexpression of Runx3 could restore the Th1/Th2 balance; miR-371, miR-138, miR-544, miR-145, and miR-214 could directly bind to the 3’-UTR of Runx3. All these findings suggest that these miRNAs may be involved in Th1/Th2 imbalance in asthma by regulating Runx3 [34]. One study used predictive algorithms dentified potential direct miR-21 targets among IL-13-regulated lung transcripts such as IL-12p35 mRNA that was decreased in IL-13 transgenic mice. MiR-21 was significantly elevated in ovalbumin-induced mice lungs, suggesting that miR-21 regulates Th1 to Th2 phenotypic transformation by decreasing the mouse IL-12p35 transcriptome [16]. Reduced levels of miR-29b were found in the lungs and spleens of OVA-induced asthmatic mice, and this miRNA indirectly affects the Th2 response by regulating the production of T-box transcription factors and IFN-γ in T helper cells [35]. Low expression of miR-29b in asthmatic lung can increase the production of IFN-γ and restore the balance of Th1/Th2 in asthmatic lung [36]. The researchers evaluated the relationship between miRNA levels in small extracellular vesicles (sEVs) from nasal washing and pulmonary function parameters in children with mild to moderate or severe asthma compared to healthy controls. The results showed that lower levels of miR-34a, miR-92b and miR-210 in children with sEVs in this study were associated with pulmonary function and airway obstruction. Subsequent functional pathway analysis showed reduced levels of miR-92b, miR-210, and miR-34a in epithelial-derived sEVs in asthma, and these miRNAs regulate Th2 polarization and dendritic cell maturation [37].
2.3 miRNAs regulation of Th2 differentiation via signaling pathways
Inhibition of microRNA-126 (miR-126) has been shown to effectively inhibit Th2-driven airway inflammation, mucus hypersecretion, and airway hyperresponsiveness in a model of ovalbumin (OVA) -induced chronic asthma [38]. The blocking of miR-126 leads to the enhanced expression of POU domain 2 related factor 1, which activates the transcription factor PU1, that changes the function of Th2 cells by negatively regulating the expression of GATA3 [39]. In childhood asthma, miRNA-451a was found to inhibit Th2 cell differentiation by down-regulating proto-oncogene 1 (ETS1). This study reveals that miRNA-451a-ETS1 axis dysfunction is a novel molecular mechanism that underlies the pathogenesis of childhood asthma [40]. A study has shown that miR-1165-3p targets IL-13 and PPM1A to control Th2 differentiation and pulmonary inflammation in asthma. miR-1165-3p inhibits the Th2 response of allergy through the STAT and AKT signaling pathways by targeted inhibition of protein phosphatase, Mg 2+/Mn 2+ − dependent 1A (PPM1A), thus proving that miR-1165-3p and PPM1A may be effective targets for the prevention and treatment of allergic asthma and related diseases [41]. The miR-29c/B7-H3 axis plays an important role in asthmatic children by regulating Th2/Th17 cell differentiation, and may provide a new target for asthma treatment [42]. The role of Th2-mediated microRNAs in asthma are summarized in the Table 1 (Figure 1).
Regulation of Th2 in asthma by miRNAs. Th1 and Th2 are in equilibrium. miR-34a, miR-92b and miR-210 regulate Th2 polarization. MiRNAs such as miR-371, miR-138, miR-544 and miR-145 affect Th1/Th2 balance of asthma by regulating Runx3. MiR-21 regulates Th1 and Th2 balance by regulating IL-12p35 transcripts. As shown in the figure, miR-24, miR-27, miR-410, let-7a, miR-145, miR-146a, miR-1248 and other miRNAs regulate the secretion of Th2 cytokines, such as IL-4, IL-5 and IL-13, through up-regulation or down-regulation in asthma, and affect the occurrence and development of asthma.
LncRNA refers to a class of RNA molecules with a length greater than 200 nucleotides which do not have the function of coding RNAs. LncRNAs are mainly involved in gene expression regulation at the transcription, post-transcription, translation and epigenetic levels, and are widely involved in various life processes such as cell proliferation, differentiation, apoptosis, migration, aging and metabolism [45, 46]. Abundant expressions of lncRNAs were found in T cell lineages, suggesting that these transcripts play important roles in T cell development and differentiation [47]. Studies have found that some lncRNAs play important roles in the pathogenesis of asthma by regulating Th1/Th2 balance and Th2 inflammatory response [3, 48]. Understanding how lncRNAs alter gene expression to promote Th2 skewing may provide new insights into mechanisms and therapeutic targets for asthma.
3.1 Regulation of Th1/Th2 balance by lncRNAs
The gene encoding lncRNA MALTA1, a highly conserved nuclear lncRNA, is located on chromosome 11 (11q13.1). MALTA1 is highly expressed in most cells [49]. Liang et al. [50] conducted a cohort study of 772 asthmatic patients and 441 healthy controls, and found that the expression of MALAT1 was up-regulated and the expression of miR-155 was down-regulated in the blood of asthmatic patients. MALAT1 expression was inversely associated with impaired lung function and the Th1 / Th2 ratio, suggesting that its role was to impairs lung function by promoting the Th2 response. That is, the up-regulated expression of MALAT1 can induce the production of Th2 cytokines and inhibit the release of Th1 cytokines. Further study of the experiment showed that MALAT1 sponging miR-155 could alter the Th1/Th2 balance within CD4+ T cells through cytotoxic T-lymphocyte antigen 4 (CTLA-4) dependent mechanism. This study highlights the novel role of lncRNA MALTA1 in the development of Th2 in asthma. Wei et al. found that lncRNA PVT1 expression was increased in ozone-induced mouse asthma models, and the lncRNA PVT1-miR-15a-5p axis promoted Th1/Th2 imbalance in CD4 + T cells by activating the PI3K-Akt- signaling pathway [51].
3.2 lncRNA regulate Th2-type inflammation in asthma
Zhu et al. assessed expression of lncRNAs in peripheral blood samples of patients with eosinophilic asthma, neutrophilic asthma and healthy controls using RNA-sequencing. In this study, it was found that the expression of LNC_000127 was increased in eosinophilic asthma, and knockdown of LNC_000127 (refer to this article for details) reduced the expression of CCR8, CRLF2, and CD40L (Th2 inflammatory receptor). Targeting LNC_000127 may effectively reduce Th2 inflammation in eosinophilic asthma [52]. It has been demonstrated that induced pluripotent stem cells (iPSCs)-mesenchymal stem cells (MSCs) can effectively inhibit airway allergic inflammation in mice, and significantly reduce the expression levels of immunoglobulin (Ig) E and Th2 cytokines [53]. Further studies by Wang et al. [54] found that lncRNA MM9lincrnaexon12105 + and AK089315 were up-regulated in a model of ova-induced asthma. These two lncRNAs may be the main therapeutic targets of induced pluripotent stem cell mesenchymal stem cells (iPSC-MSCs) and may be involved in the regulation of Th2 type inflammation in asthma. This study provides an important basis for the study of the potential mechanisms of airway allergic inflammation and iPSC-MSC immune regulation, and these abnormal lncRNAs may become potential targets of allergic inflammation and iPSC-MSC mediated immune regulation. Wang et al. [55] conducted next-generation sequencing analysis of lncRNA and mRNAs on CD4 + T cells from ovalbumin-induced acute asthma mice and control mice, constructed co-expression networks of lncRNA and mRNAs, and found that lncRNA Fantom3_9230106C11 was decreased in Th2 cells. Further qRT-PCR verification showed that lncRNA Fantom3_9230106C11 could regulate the differentiation of Th2 cells. This study provides a platform to elucidate the role of lncRNA in Th2 differentiation and the pathogenesis of asthma. The role of Th2-mediated lncRNA in asthma are summarized in the Table 2 (Figure 2).
lncRNA regulate Th2 response in asthma. MALAT1 sponging miR-155 could alter the Th1/Th2 balance within CD4+ T cells through CTLA-4 dependent mechanism. lncRNA PVT1-miR-15a-5p axis promoted Th1/Th2 imbalance in CD4 + T cells by activating the PI3K-Akt- signaling pathway. LNC_000127, MM9lincrnaexon12105 + and AK089315 and lncRNA Fantom3_9230106C11 primarily regulate the Th2-type inflammation.
CircRNAs compose a novel class of ncRNAs characterized by covalently closed-loop structures [56]. CircRNAs typically act as molecular sponges to bind and inhibit the transcription or activity of microRNAs (miRNAs), thereby affecting downstream mRNA expression [57]. CircRNAs are involved in the pathogenesis of various diseases [58]. The role of circRNA in asthma regulation is still in its infancy, and there are relatively few studies on the role of circRNA in the pathogenesis of asthma, especially Th2 inflammation in asthma.
Huang et al. [59] confirmed the expression of hsa_circ_0002594 in CD4 + T cells in asthmatic patients and healthy subjects by quantitative real-time PCR (qRT-PCR) using circRNA microarray analysis (such as a student’s t test, nonparametric tests, Spearman’s rank-order correlation, Fisher’s exact test, and the generation of receiver operating characteristic curves). Their data suggest that hsa_circ_0002594 is upregulated in CD4 + T cells of asthmatic patients, which may have potential value in the diagnosis and treatment of Th2-mediated allergic asthma. In a mouse model of HDM-induced asthma, the results revealed that the relative expression levels of circ_0000629 and circ_0000455 in the asthma group were significantly increased compared with those animals in the control group, whereas the expression levels of circ_0000454 and circ_0000723 were significantly decreased [60]. The circRNA-miRNA regulatory network indicated that two of the downregulated circRNAs (circ_0001454 and circ_0000723) targeted miR-146b and miR-214, and two of these upregulated circRNAs (circ_0000455 and circ_0000629) could target miR-29b and miR-15a [60]. The expression levels of inducible co-stimulator, a target gene of miR-29b, were also previously shown to be elevated in the lungs of asthmatic mice, and promoted Th2 cytokine production and eosinophilic inflammation [61]. Furthermore, vascular endothelial growth factor, which is a target gene of mir-15a, was shown to be overexpressed in cases of Th2-mediated lung inflammation, such as asthma, and induced an asthma-like phenotype [62]. By contrast, two of the downregulated circRNAs (circ_0001454 and circ_0000723) targeted miR-146b and miR-214, respectively, which were previously shown to be positively associated with asthma [34, 63]. Huang et al. found that hsa_circ_0005519 may induce IL-13 and IL-6 expression by regulating hsa-let-7a-5p in CD4+ T cells to affect asthma. And hsa_circ_0005519 may be a potential biomarker of asthma [64]. The role of Th2-mediated circRNAs in asthma are summarized in the Table 3 (Figure 3).
Altered circRNA
Expressi-on pattern
Targets/Regul-ators
Signaling Pathway
Function
Ref
hsa_circ_0002594
Up-regulated
—
—
diagnosis and treatment of Th2-mediated allergic asthma
circRNAs regulate Th2 response in asthma. Hsa_circ_0005519 functions as an endogenous hsa-let-7a-5p sponge to regulate the hsa-let-7a-5p/IL-13/IL-6 pathway in CD4+ T cells. Two down-regulated circRNAs (circ_0001454 and circ_0000723) targeted miR-146b and miR-214, while two up-regulated circRNAs (circ_0000455 and circ_0000629) targeted miR-29b and miR-15a. These four circRNAs regulate TH2 cytokine production by targeting miRNA.
NcRNAs display a wide range of functions, and each ncRNA has its own characteristics. This chapter mainly summarized the regulation of Th2 differentiation and immune response in asthma and experimental models of disease.
The role of miRNA in regulating Th2 cell-mediated inflammation in asthma is mainly reflected in several aspects: regulating Th1/Th2 balance, influencing cytokine secretion and regulating the activation state of T cells. The pathway of regulation can be that a single miRNA regulates one or more mRNAs, or multiple miRNAs of one or more gene clusters synergistically act on one or more mRNAs to exert biological effects. LncRNA plays a similar role to miRNA in regulating Th2 cell-mediated inflammation in asthma, affecting its activation, transformation and cytokine secretion. Most of the existing studies only analyzed the expression profile of lncRNA and identified the differentially expressed lncRNA molecules, but did not conduct in-depth study on its precise molecular mechanism. CircRNAs may play important roles in Th2 cells differentiation and, thus, play regulatory roles in Th2 cell-mediated inflammation in asthma. They can act as competitive endogenous RNAs (ceRNAs, which can regulate each other by competitively binding common microRNA response elements) of miRNAs to exert their biological effects, but the specific mechanism needs to be further studied.
In conclusion, miRNA, lncRNA and circRNA play important roles in regulation of Th2 cell function in asthma. However, the exact molecular mechanism of ncRNA in the regulation of TH2 cell function in asthma remains to be determined. Therefore, how to find out functional ncRNAs and elucidate their precise functions present the difficulties and challenges in the study of ncRNAs in this field. In future, more and more ncRNAs involved in the pathogenesis of asthma will be discovered, and the role of ncRNAs in the inflammatory process mediated by Th2 cells will be revealed. This will provide new details in the pathogenesis of asthma, and will help to develop new biomarkers and molecular targets for the diagnosis, classification, and treatment of asthma.
1.Pavord ID, Beasley R, Agusti A, Anderson GP, Bel E, Brusselle G, Cullinan P, Custovic A, Ducharme FM, Fahy JV, Frey U, Gibson P, Heaney LG, Holt PG, Humbert M, Lloyd CM, Marks G, Martinez FD, Sly PD, von Mutius E, Wenzel S, Zar HJ, Bush A. After asthma: redefining airways diseases. Lancet. 2018 Jan 27;391(10118):350-400
2.E.D. Bateman, S.S. Hurd, P.J. Barnes, J. Bousquet, J.M. Drazen, J.M. FitzGerald, P. Gibson, K. Ohta, P. O'Byrne, S.E. Pedersen, E. Pizzichini, S.D. Sullivan, S.E. Wenzel, H.J. Zar, Global strategy for asthma management and prevention: GINA executive summary, Eur Respir J, 31 (2008) 143-178
3.Ghafouri-Fard S, Shoorei H, Taheri M, Sanak M. Emerging role of non-coding RNAs in allergic disorders. Biomed Pharmacother. 2020 Oct; 130:110615
4.Moharamoghli M, Hassan-Zadeh V, Dolatshahi E, Alizadeh Z, Farazmand A. The expression of GAS5, THRIL, and RMRP lncRNAs is increased in T cells of patients with rheumatoid arthritis. Clin Rheumatol. 2019 Nov;38(11):3073-3080
5.Zhou R, Wu Y, Wang W, Su W, Liu Y, Wang Y, Fan C, Li X, Li G, Li Y, Xiong W, Zeng Z. Circular RNAs (circRNAs) in cancer. Cancer Lett. 2018 Jul 1; 425:134-142
6.Foster PS, Maltby S, Rosenberg HF, Tay HL, Hogan SP, Collison AM, Yang M, Kaiko GE, Hansbro PM, Kumar RK, Mattes J. Modeling TH 2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma. Immunol Rev. 2017 Jul;278(1):20-40
7.Mukherjee M, Nair P. Autoimmune Responses in Severe Asthma. Allergy Asthma Immunol Res. 2018 Sep;10(5):428-447
9.Kannan AK, Sahu N, Mohanan S, Mohinta S, August A. IL-2-inducible T-cell kinase modulates TH2-mediated allergic airway inflammation by suppressing IFN-γ in naive CD4+ T cells. J Allergy Clin Immunol. 2013 Oct;132(4):811-20. e1-5
10.Zhang B, Farwell MA. microRNAs: a new emerging class of players for disease diagnostics and gene therapy. J Cell Mol Med. 2008 Jan-Feb;12(1):3-21
11.Pauley KM, Cha S, Chan EK. MicroRNA in autoimmunity and autoimmune diseases. J Autoimmun. 2009 May-Jun;32(3-4):189-94
12.Gebert LFR, MacRae IJ. Regulation of microRNA function in animals. Nat Rev Mol Cell Biol. 2019 Jan;20(1):21-37
13.Rebane A, Akdis CA. MicroRNAs in allergy and asthma. Curr Allergy Asthma Rep. 2014 Apr;14(4):424
14.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. J Allergy Clin Immunol. 2011 Jul;128(1):160-167.e4
15.Pua HH, Steiner DF, Patel S, Gonzalez JR, Ortiz-Carpena JF, Kageyama R, Chiou NT, Gallman A, de Kouchkovsky D, Jeker LT, McManus MT, Erle DJ, Ansel KM. MicroRNAs 24 and 27 Suppress Allergic Inflammation and Target a Network of Regulators of T Helper 2 Cell-Associated Cytokine Production. Immunity. 2016 Apr 19;44(4):821-32
16.Lu TX, Munitz A, Rothenberg ME. MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression. J Immunol. 2009 Apr 15;182(8):4994-5002
17.Panganiban RP, Pinkerton MH, Maru SY, Jefferson SJ, Roff AN, Ishmael FT. Differential microRNA epression in asthma and the role of miR-1248 in regulation of IL-5. Am J Clin Exp Immunol. 2012 Nov 15;1(2):154-65
18.Borish L, Aarons A, Rumbyrt J, Cvietusa P, Negri J, Wenzel S. Interleukin-10 regulation in normal subjects and patients with asthma. J Allergy Clin Immunol. 1996 Jun;97(6):1288-96
19.Sharma A, Kumar M, Ahmad T, Mabalirajan U, Aich J, Agrawal A, Ghosh B. Antagonism of mmu-mir-106a attenuates asthma features in allergic murine model. J Appl Physiol (1985). 2012 Aug;113(3):459-64
20.Simpson LJ, Patel S, Bhakta NR, Choy DF, Brightbill HD, Ren X, Wang Y, Pua HH, Baumjohann D, Montoya MM, Panduro M, Remedios KA, Huang X, Fahy JV, Arron JR, Woodruff PG, Ansel KM. A microRNA upregulated in asthma airway T cells promotes TH2 cytokine production. Nat Immunol. 2014 Dec;15(12):1162-70
21.Han S, Ma C, Bao L, Lv L, Huang M. miR-146a Mimics Attenuate Allergic Airway Inflammation by Impacted Group 2 Innate Lymphoid Cells in an Ovalbumin-Induced Asthma Mouse Model. Int Arch Allergy Immunol. 2018;177(4):302-310
22.Zech A, Ayata CK, Pankratz F, Meyer A, Baudiß K, Cicko S, Yegutkin GG, Grundmann S, Idzko M. MicroRNA-155 modulates P2R signaling and Th2 priming of dendritic cells during allergic airway inflammation in mice. Allergy. 2015 Sep;70(9):1121-9
23.Zhou H, Li J, Gao P, Wang Q , Zhang J. miR-155: A Novel Target in Allergic Asthma. Int J Mol Sci. 2016 Oct 24;17(10):1773
24.Kumar M, Ahmad T, Sharma A, Mabalirajan U, Kulshreshtha A, Agrawal A, Ghosh B. Let-7 microRNA-mediated regulation of IL-13 and allergic airway inflammation. J Allergy Clin Immunol. 2011 Nov;128(5):1077-85. e 1-10
25.Jin R, Hu S, Liu X, Guan R, Lu L, Lin R. Intranasal instillation of miR-410 targeting IL-4/IL-13 attenuates airway inflammation in OVA-induced asthmatic mice. Mol Med Rep. 2019 Feb;19(2):895-900
26.Huang XP, Qin CY, Gao YM. miR-135a inhibits airway inflammatory response in asthmatic mice via regulating JAK/STAT signaling pathway. Braz J Med Biol Res. 2021 Jan 15;54(3): e10023
27.Grünig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, Rennick DM, Sheppard D, Mohrs M, Donaldson DD, Locksley RM, Corry DB. Requirement for IL-13 independently of IL-4 in experimental asthma. Science. 1998 Dec 18;282(5397):2261-3
28.Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, Donaldson DD. Interleukin-13: central mediator of allergic asthma. Science. 1998 Dec 18;282(5397):2258-61
29.Kuperman DA, Huang X, Koth LL, Chang GH, Dolganov GM, Zhu Z, Elias JA, Sheppard D, Erle DJ. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat Med. 2002 Aug;8(8):885-9
30.Solberg OD, Ostrin EJ, Love MI, Peng JC, Bhakta NR, Hou L, Nguyen C, Solon M, Nguyen C, Barczak AJ, Zlock LT, Blagev DP, Finkbeiner WE, Ansel KM, Arron JR, Erle DJ, Woodruff PG. Airway epithelial miRNA expression is altered in asthma. Am J Respir Crit Care Med. 2012 Nov 15;186(10):965-74
31.Zhang K, Liang Y, Feng Y, Wu W, Zhang H, He J, Hu Q , Zhao J, Xu Y, Liu Z, Zhen G. Decreased epithelial and sputum miR-221-3p associates with airway eosinophilic inflammation and CXCL17 expression in asthma. Am J Physiol Lung Cell Mol Physiol. 2018 Aug 1;315(2): L253-L264
32.Shi ZG, Sun Y, Wang KS, Jia JD, Yang J, Li YN. Effects of miR-26a/miR-146a/miR-31 on airway inflammation of asthma mice and asthma children. Eur Rev Med Pharmacol Sci. 2019 Jun;23(12):5432-5440
33.Kılıç A, Santolini M, Nakano T, Schiller M, Teranishi M, Gellert P, Ponomareva Y, Braun T, Uchida S, Weiss ST, Sharma A, Renz H. A systems immunology approach identifies the collective impact of 5 miRs in Th2 inflammation. JCI Insight. 2018 Jun 7;3(11): e97503
34.Qiu YY, Zhang YW, Qian XF, Bian T. miR-371, miR-138, miR-544, miR-145, and miR-214 could modulate Th1/Th2 balance in asthma through the combinatorial regulation of Runx3. Am J Transl Res. 2017 Jul 15;9(7):3184-3199
35.Steiner DF, Thomas MF, Hu JK, Yang Z, Babiarz JE, Allen CD, Matloubian M, Blelloch R, Ansel KM. MicroRNA-29 regulates T-box transcription factors and interferon-γ production in helper T cells. Immunity. 2011 Aug 26;35(2):169-81
36.Yan J, Zhang X, Sun S, Yang T, Yang J, Wu G, Qiu Y, Yin Y, Xu W. miR-29b Reverses T helper 1 cells/T helper 2 cells Imbalance and Alleviates Airway Eosinophils Recruitment in OVA-Induced Murine Asthma by Targeting Inducible Co-Stimulator. Int Arch Allergy Immunol. 2019;180(3):182-194
37.Bartel S, La Grutta S, Cilluffo G, Perconti G, Bongiovanni A, Giallongo A, Behrends J, Kruppa J, Hermann S, Chiang D, Pfaffl MW, Krauss-Etschmann S. Human airway epithelial extracellular vesicle miRNA signature is altered upon asthma development. Allergy. 2020 Feb;75(2):346-356
38.Collison A, Herbert C, Siegle JS, Mattes J, Foster PS, Kumar RK. Altered expression of microRNA in the airway wall in chronic asthma: miR-126 as a potential therapeutic target. BMC Pulm Med. 2011 May 23; 11:29
39.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. Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18704-9
40.Wang T, Zhou Q , Shang Y. Downregulation of miRNA-451a Promotes the Differentiation of CD4+ T Cells towards Th2 Cells by Upregulating ETS1 in Childhood Asthma. J Innate Immun. 2021;13(1):38-48
41.Wang Z, Ji N, Chen Z, Sun Z, Wu C, Yu W, Hu F, Huang M, Zhang M. MiR-1165-3p Suppresses Th2 Differentiation via Targeting IL-13 and PPM1A in a Mouse Model of Allergic Airway Inflammation. Allergy Asthma Immunol Res. 2020 Sep;12(5):859-876
42.Zhang X, Zhao X, Sun H, Yan Y, Huang L, Gu W, Jiang W, Wang Y, Zhu C, Ji W, Hao C, Chen Z. The role of miR-29c/B7-H3 axis in children with allergic asthma. J Transl Med. 2018 Aug 3;16(1):218
43.Sawant DV, Wu H, Kaplan MH, Dent AL. The Bcl6 target gene microRNA-21 promotes Th2 differentiation by a T cell intrinsic pathway. Mol Immunol. 2013 Jul;54(3-4):435-42
44.Long CM, Lukomska E, Marshall NB, Nayak A, Anderson SE. Potential Inhibitory Influence of miRNA 210 on Regulatory T Cells during Epicutaneous Chemical Sensitization. Genes (Basel). 2016 Dec 27;8(1):9
45.Yang L, Lin C, Jin C, Yang JC, Tanasa B, Li W, Merkurjev D, Ohgi KA, Meng D, Zhang J, Evans CP, Rosenfeld MG. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature. 2013 Aug 29;500(7464):598-602
46.Kim J, Kim KM, Noh JH, Yoon JH, Abdelmohsen K, Gorospe M. Long noncoding RNAs in diseases of aging. Biochim Biophys Acta. 2016 Jan;1859(1):209-21
47.Hu G, Tang Q , Sharma S, Yu F, Escobar TM, Muljo SA, Zhu J, Zhao K. Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation. Nat Immunol. 2013 Nov;14(11):1190-8
48.Narożna B, Langwiński W, Szczepankiewicz A. Non-Coding RNAs in Pediatric Airway Diseases. Genes (Basel). 2017 Nov 27;8(12):348
49.Ji P, Diederichs S, Wang W, Böing S, Metzger R, Schneider PM, Tidow N, Brandt B, Buerger H, Bulk E, Thomas M, Berdel WE, Serve H, Müller-Tidow C. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 2003 Sep 11;22(39):8031-41
50.Liang Z, Tang F. The potency of lncRNA MALAT1/miR-155/CTLA4 axis in altering Th1/Th2 balance of asthma. Biosci Rep. 2020 Feb 28;40(2): BSR20190397
51.Wei Y, Han B, Dai W, Guo S, Zhang C, Zhao L, Gao Y, Jiang Y, Kong X. Exposure to ozone impacted Th1/Th2 imbalance of CD4+ T cells and apoptosis of ASMCs underlying asthmatic progression by activating lncRNA PVT1-miR-15a-5p/miR-29c-3p signaling. Aging (Albany NY). 2020 Nov 20;12(24):25229-25255
52.Zhu Y, Mao D, Gao W, Han G, Hu H. Analysis of lncRNA Expression in Patients With Eosinophilic and Neutrophilic Asthma Focusing on LNC_000127. Front Genet. 2019 Mar 19;10: 141
53.Y.Q . Sun, M.X. Deng, J. He, Q .X. Zeng, W. Wen, D.S. Wong, H.F. Tse, G. Xu, Q . Lian, J. Shi, Q .L. Fu, Human pluripotent stem cell-derived mesenchymal stem cells prevent allergic airway inflammation in mice, Stem Cells, 30 (2012) 2692-2699
54.Wang SY, Fan XL, Yu QN, Deng MX, Sun YQ , Gao WX, Li CL, Shi JB, Fu QL. The lncRNAs involved in mouse airway allergic inflammation following induced pluripotent stem cell-mesenchymal stem cell treatment. Stem Cell Res Ther. 2017 Jan 6;8(1):2
55.Wang Z, Ji N, Chen Z, Wu C, Sun Z, Yu W, Hu F, Huang M, Zhang M. Next Generation Sequencing for Long Non-coding RNAs Profile for CD4+ T Cells in the Mouse Model of Acute Asthma. Front Genet. 2019 Jun 7; 10:545
56.Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, Loewer A, Ziebold U, Landthaler M, Kocks C, le Noble F, Rajewsky N. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013 Mar 21;495(7441):333-8
57.Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J. Natural RNA circles function as efficient microRNA sponges. Nature. 2013 Mar 21;495(7441):384-8
58.Vidal AF, Sandoval GT, Magalhães L, Santos SE, Ribeiro-dos-Santos Â. Circular RNAs as a new field in gene regulation and their implications in translational research. Epigenomics. 2016 Apr;8(4):551-62
59.Huang Z, Fu B, Qi X, Xu Y, Mou Y, Zhou M, Cao Y, Wu G, Xie J, Zhao J, Wang Y, Xiong W. Diagnostic and Therapeutic Value of Hsa_circ_0002594 for T Helper 2-Mediated Allergic Asthma. Int Arch Allergy Immunol. 2020 Dec 16:1-11
60.Bao H, Zhou Q , Li Q , Niu M, Chen S, Yang P, Liu Z, Xia L. Differentially expressed circular RNAs in a murine asthma model. Mol Med Rep. 2020 Dec;22(6):5412-5422
61.Gonzalo JA, Tian J, Delaney T, Corcoran J, Rottman JB, Lora J, Al-garawi A, Kroczek R, Gutierrez-Ramos JC, Coyle AJ. ICOS is critical for T helper cell-mediated lung mucosal inflammatory responses. Nat Immunol. 2001 Jul;2(7):597-604
62.Lee CG, Link H, Baluk P, Homer RJ, Chapoval S, Bhandari V, Kang MJ, Cohn L, Kim YK, McDonald DM, Elias JA. Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nat Med. 2004 Oct;10(10):1095-103
63.Feng MJ, Shi F, Qiu C, Peng WK. MicroRNA-181a, −146a and -146b in spleen CD4+ T lymphocytes play proinflammatory roles in a murine model of asthma. Int Immunopharmacol. 2012 Jul;13(3):347-53
64.Huang Z, Cao Y, Zhou M, Qi X, Fu B, Mou Y, Wu G, Xie J, Zhao J, Xiong W. Hsa_circ_0005519 increases IL-13/IL-6 by regulating hsa-let-7a-5p in CD4+ T cells to affect asthma. Clin Exp Allergy. 2019 Aug;49(8):1116-1127
Written By
Yanhua Niu, Chao Wang, Xiaoyan Dong and Nanbert Zhong
Submitted: 17 February 2021Reviewed: 19 March 2021Published: 16 April 2021
Open access peer-reviewed chapter
