Asthma is a heterogenous disease with complex pathogenesis and various phenotypes which can be reclassified via molecular biomarkers called “endotypes” (Bond et al., 2018; Assaf and Hanania, 2019). At present, asthma endotypes are divided into T-helper-2(Th2)-high (eosinophilic) and Th2-low (non-eosinophilic). The ratio tilt of T lymphocyte subsets (Th1/Th2) is the most important pathogenesis of asthma (Tang et al., 2018b). Th2-high asthma is related to adaptive immunity and allergic asthma (Lampalo et al., 2019; Song et al., 2019). Upon allergens stimulation, dendritic cells (DCs) activate T-helper-2 (Th2) cells to secrete Th2 cytokines such as IL-4, IL-5 and IL-13 which act on airway epithelial cells, eosinophils, B lymphocytes and other inflammatory cells. This drives B cells to produce a large number of IgE that cross-linking causes degranulation of mast cells to produce a series of inflammatory mediators such as leukotrienes, endothelin, prostaglandin and thromboxane A2, etc. and eventually induce rapid onset (increased IgE) allergies and eosinophilic airway inflammation (Bégin and Nadeau, 2014; Chogtu et al., 2016; McCracken et al., 2016). Studies have shown that childhood asthma is associated with eosinophils in the airways, allergic sensitization and adaptive immunity (Kim et al., 2010). Th2 cells concretely activated by allergens via secreting Th2 cytokines IL-4, IL-5 and IL-13, amplify type II inflammation, while T helper 1 (Th1) cells by secreting Th1 cytokines such as IFN-γ, IL-2, lymphotoxin (LT)-α and tumor necrosis factor (TNF)-α and so on, limit type II inflammation and mediate type I inflammation (Foster et al., 2017; Mukherjee and Nair, 2018), which causing childhood asthma. Consequently, the imbalance of the ratio of T lymphocyte subsets (Th1/Th2) is the key mechanism of childhood asthma, whether it is innate immunity or adaptive immunity.

However, non-Th2-type asthma related to non-allergic asthma, which is characterized by emotion, obesity, environmental factors, such as air pollution including ozone, cigarette smoke and so on, may release cytokines such as Il-17 and IFN-γ by activation of Th1 cells, leading to neutrophilic inflammation, M1 macrophage, NKT cell recruitment to the airways and AHRs (Castan et al., 2020; Agache et al., 2021). Nevertheless, non-Th2-type asthma characterized by type I innate lymphoid cells (ILC1) and type III innate lymphoid cells activation (ILC3) is most common in adult asthma. ILC1 in asthma patients promoted eosinophil apoptosis and inhibited eosinophilic airway inflammation (Barnig et al., 2013; Barnig and Levy, 2015). ILC3 produced IL-17A and caused obesity-related AHR effects (Kim et al., 2014). Furthermore, other cytokines (such as IL-17, IL-21, IL-22) also accelerated mucus secretion of airway smooth muscle cells, increased the production of cytokines and chemokines, and promoted neutrophil recruitment by inducing CXC chemokines (Lejeune et al., 2020). In addition, IL-17 promoted airway remodeling by increasing the production of fibrotic cytokines, angiogenic factors, proteases and collagen.

Moreover, airway epithelial cells and type II innate lymphoid cells (ILC2) are also involved in adaptive immune. After allergens exposure, epithelial cells polarize macrophages, DC cells, T cells, etc. (Frati et al., 2018; Lejeune et al., 2020), releasing not only IL-4, IL-5, IL-13 and other cytokines but also pro-inflammatory cytokines such as IL-25, IL-33 and thymic stromal lymphopoietin (TSLP) activating ILC2 rather than IFN-γ and TNF-β produced by Th1 cells (Lejeune et al., 2020), which causes Th0 cells polarized into Th2 cells in asthma-specific cytokine environments, resulting in a balanced skewed Th2 cellular immune response. The immune response of Th2 cells further induced changes in the pathophysiological characteristics of asthma, including eosinophils mobilizing IgE, secreting excessive mucus, smooth muscle proliferation and airflow obstruction. Additionally, under the effect of IL-5, eosinophils entered the respiratory tract and triggered a second inflammatory response (Deschildre et al., 2017; Gao et al., 2017). Studies have shown that CD4⁺ T cells are essential for inducing allergic airway disease in newborns, and ILC2s are very important in the pathogenesis of allergic airway disease in adults. Mechanistically, CD4⁺ T cells and ILC2s regulate asthma by promoting the production of IL-13 amplifying type II inflammation (Saglani et al., 2018) (Figure 2). Therefore, understanding the role of immune factors in the development and regulation of asthma will provide opportunities for asthma treatment.

Neural signaling pathway also has appealing potential as an application to study pathways to childhood asthma development. Molecular studies have indicated that Mitogen-activated protein kinase (MAPK) pathways, including extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase (JNK), are involved in the inflammatory response and development of airway remodeling during childhood asthma (Lee et al., 2019b; Jia et al., 2019). Concretely, ERK1/2 is involved in airway remodeling (Defnet et al., 2019), while p38 MAPK and JNK are considered as anti-inflammation targets to regulate inflammatory processes via phosphorylation of downstream mediators in childhood asthma (Kim and Choi, 2010; Pulido and Lang, 2019; Theodorou et al., 2022). However, literatures about the pathogenesis of MAPK pathways in childhood asthma are limited. In this review we mainly focus on the roles of MAPK signaling pathways in the pathogenesis and related treatment of childhood asthma.

Experiment shows ERK1/2 signaling mainly acts on airway epithelial cells and smooth muscle cells of asthmatic mice (Liu et al., 2008). Concretely, ERK1/2 inducible proteins Jun b proto-oncogene (JunB) mediates ERK1/2 activation via the AP-1 complex, which increases the expression of several Th2 cytokines and drives Th2 cell differentiation, causing childhood asthma (Alam and Gorska, 2011). Besides, sprouty-2, a cytosolic adapter protein, also regulates receptor-mediated ERK1/2 activation by preventing c-Cbl-mediated degradation of EGF receptor, which also stimulates Th2 cell differentiation to amplify Th2 inflammation (Liu et al., 2008; Alam and Gorska, 2011; Sripada et al., 2021). However, further mechanism about ERK1/2 in childhood asthma is needed to explore.

In contrast to ERK1/2, p38 MAPKs and the JNK pathways favor Th1 differentiation. P38 MAPK and JNK activation contributes to the inflammatory response in asthma. Moreover, p38 MAPK is observed in the basal layer of the columnar epithelium, alveolar macrophage and bronchial epithelial, ect. driving basal metabolic processes for these cell type. That’s to say, p38 MAPK is vital for allergen induced epithelial production of IL-25 and thymic stromal lymphopoietin (TSLP), further mediating the type-2 allergic response in asthma (Yu et al., 2010; Lin et al., 2015; Southworth et al., 2018). Previous studies have confirmed that dual-specificity phosphatase1 (DUSP1) also plays vital role in anti-inflammation by deactivating MAPKs through dephosphorylation (Pulido and Lang, 2019; Xin et al., 2021; Theodorou et al., 2022; Xing and Wong, 2022). Besides, Studies have confirmed that JNK is essential for airway inflammation via modulating RAGE/β-catenin signaling (Huang et al., 2021a). Regretfully, further mechanisms between JNK and RAGE/β-catenin is deserved exploring (Figure 3).

Although the immune mechanisms and signaling pathways of asthma are widely reported, complex interactions between genetic susceptibility and environmental influences also lead to childhood asthma (Thomsen, 2015). Studies have shown that the genetic susceptibility of asthma can be as high as 60–70%, which suggests that understanding the genetic basis of childhood asthma might unravel mechanisms, directing the treatment of asthma. So further genome-wide association studies (GWAS) is imminent due to the complexity and heterogeneity of asthma (Alizadeh et al., 2017; Kabesch and Tost, 2020). Consequently, it has been found that the main genetic risk factor for asthma is single nucleotide polymorphism (SNPs), which is a single-base pair, occurring on average one in 300 nucleotides (Lee et al., 2015). Asthma-associated SNPs in this locus are related to levels of mRNA expression of ORMDL3 in lymphoblastic cell lines using eQTL mapping, which associates SNPs with gene expression (El-Husseini et al., 2020). Non-synonymous SNP of The IL7R (rs6897932) and IL2RB (rs2284033) (Arenas-Ramirez et al., 2015) regulate asthma by regulating type II inflammation via activating three pathways: JAK-STAT, PI3K-Akt-mTOR (Patel and Chang, 2012), and MEK-ERK (El-Husseini et al., 2020). Approximately 88% of the disease-associated variants acquired from genome-wide association studies (GWASs) reside in non-coding regions (El-Husseini et al., 2020). Examples of pathways or networks that are implicated by GWASs in asthma are the IL33-IL1-RL1 receptor pathway, leading to eosinophilia, and the T-helper-2 (Th2) cytokine IL-5 and IL-4RA receptor, leading to eosinophilia and type 2 inflammation or viral response (CDHR3, ORMDL3⁾ (Zhang et al., 2019a; Basnet et al., 2019). For example, genetic variation at chromosome 17q12-21 is associated with childhood asthma but not adult asthma (Ferreira et al., 2019; Pividori et al., 2019). Subsequent investigations also linked SNPs at this locus to GSDMA, GSDMB, CRKRS, ZBPB2, and IKZF2 expression in whole blood cells and lung tissue.

LncRNAs, with a length of over 200 nt, play critical roles in regulating gene expression at multiple levels, including transcriptional, post-transcriptional levels, microRNA chelation and translation efficiency regulation and more (Hao and Zan, 2021; Wang et al., 2021). Although many studies have proved that lncRNAs and childhood asthma are inextricably linked (Wang et al., 2021), the roles of lncRNAs in childhood asthma remain unclear.

Recently, it has been reported that lncRNAs participate in regulating airway inflammation and remodeling (Ezegbunam and Foronjy, 2018; Liu et al., 2019a; Li et al., 2020a), and are helpful to further determine the biomarkers and therapeutic target of childhood asthma. Increasing numbers of studies suggest that lncRNAs affect the regulation of immune response, airway inflammation and cytokine expression (Dai et al., 2021). Moreover, lncRNAs also participate in the regulation of T helper (Th)1/Th2 imbalance, T regulatory (Treg)/Th17 imbalance, eosinophils dysfunction, macrophage polarization, airway smooth muscle cells (ASMCs) proliferation and so on (Zhu et al., 2020), to mediate childhood asthma.

Studies have found that LNC-000127 was not only closely related to Th2 inflammation but also positively regulated eosinophilic asthma. Malat1 has capability to modulate Th1/Th2 balance in asthma via MALAT1/miR-155/CTLA-4 axis. Therefore, MALAT1 and LNC-000127 could be used as a biomarker for eosinophilic asthma (Zhu et al., 2019). Additionally, Treg/Th17 imbalance was also associated with childhood asthma through neutrophil recruitment and exacerbation of airway inflammation, which was mediated by upregulating Th17-type cytokines (IL-17A, IL-17F) and downregulating Treg-type cytokines (IL-10, transforming growth factor (TGF-β) and so on (Westfall et al., 2021). LncRNA MEG3 regulated RORgammat expression by competitively sponge miR-17 and ultimately affected the balance of Treg/Th17 (Qiu et al., 2019; Hao and Zan, 2021; Wang et al., 2021). In addition, lncRNA RP11-401.2 upregulated in eosinophils dysfunction regulated eosinophilic asthma (Tian et al., 2018). Lnc-BAZ2B promoted M2 macrophage activation and was significantly upregulated in childhood asthma, whereas LncRNA PTPRE-AS1 was downregulated in macrophage polarization which mediated type II inflammation (Zeng et al., 2019). Regretfully, the detailed regulated mechanism of lncRNAs in childhood asthma is unclear. Besides, microarray analysis of CD4⁺ T cells of asthma patients showed that lncRNA ENST00000583179, lncRNA ENST00000579468 and lncRNA ENST00000444682 were positively correlated with the expression of IL-5 and IL-13, while lncRNA ENST00000583179 was positively correlated with the expression of IL-4 and IL-6. Interestingly, lncRNAs also regulated the expression of cytokines (IL-5 and IL-13), transcription factors (STAT5 and STAT6) and chemokines (CCL17 and CCL22), which mediated Th1 and Th2 inflammatory response in asthma. Nevertheless, its role in the pathogenesis of asthma remains to be further studied (Wang et al., 2017). Recently, lncRNAs SNHG8 and LINC01559 have been found to be directly involved in the occurrence and progression of childhood asthma through PI3K/AKT signaling pathway (Hao and Zan, 2021), and may serve as candidates for therapeutic strategies for childhood asthma (Table 2). Further elucidating the role of various lncRNAs in childhood asthma will help to understand the pathogenesis of asthma and develop potential treatment targets.

In sum, lncRNAs associated with cytokines, Th2-related transcription factors (STAT5 and STAT6) and Th2 related chemokines (CCL17 and CCL22) to affect the balance of Th1/Th2 (Wang et al., 2017). In addition, lncRNAs may act as regulator of Th1 and Th2 inflammation in the pathogenesis of asthma through lncRNA-miRNA-mRNA axis. For example, lncRNA fantom3-9230106C11 binded to miRNAs and transcription factors to mediate Th2 cell differentiation and regulated Th2 inflammation (Wang et al., 2019). However, only a small number of lncRNAs were applied to the clinical diagnosis and treatment of childhood asthma. Further research associated with lncRNAs is needed in the field of asthma therapy.

MiRNAs are a class of small ncRNAs (approximately 21–25 nucleotides) that regulate gene expression and cellular function by primarily bind to the 3′ untranslated region (3′ UTR) of mRNAs (Simpson et al., 2014; Kho et al., 2018). MiRNAs play vital roles in regulating Th2 activation, differentiation and proliferation by directly or indirectly acting on target genes (Rebane and Akdis, 2013; Qiu et al., 2018). On one hand, miRNAs regulate airway inflammation of childhood asthma by increasing Th2 cytokine secretion to decrease Th1 cytokine secretion and promote the differentiation of CD4⁺ T cells into Th2 (Midyat et al., 2016; Aripova et al., 2020). On the other hand, miRNAs also play roles in hyperplasia and hypertrophy of airway smooth muscle cells (Specjalski and Niedoszytko, 2020).

MiRNAs are involved in the pathogenesis of asthma by regulating inflammatory reaction. Specifically speaking, a core set of miRNAs were involved in childhood asthma including the downregulated let-7 family and upregulated miR-155, miR-21, miR-142-5p, miR-142-3p, miR-223, and miR-146a/b, etc. (Specjalski and Niedoszytko, 2020; van den Berge and Tasena, 2019). Let-7 microRNAs belongs to a family of highly conserved microRNA and comprises the most abundant miRNAs in lungs (Karam and Abd Elrahman, 2019; Cañas et al., 2020). Kumar et al. (2014) showed that let-7 family members were decreased in ovalbumin-sensitized animal models (Huang et al., 2020; Weidner et al., 2021), playing a proinflammatory role in asthma. Furthermore, let-7 family inhibited the secretion of IL-13 by directly targeting IL-13 transcript (Huang et al., 2020; Xu et al., 2020). Among numerous miRNAs reviewed in this field, miR-146, miR-155, and miR-223 have been identified as inflammatory response miRNAs that are up-regulated by NF-κB (Boldin and Baltimore, 2012; Kumar et al., 2014). MiRNA-21 is involved in the pathogenesis of asthma by limiting the activation of IL-12/IFN-γ and the differentiation of Th1 and Th2. It has been described that lack of miR-21 in mice may cause the increasion of levels of IFN-γ secreted by Th1 cells and the decreasion of pulmonary eosinophils, hence inhibiting the inflammation (Das et al., 2014).

MiRNAs are also involved in airway remodeling in asthmatic mice model. Ras homolog family member A (RhoA) of the Rho family GTPases regulated airway remodeling through regulating mesenchymal stem cell (MSC) differentiation. MiR-133a negatively regulated RhoA expression and bronchial smooth muscle cells (BSMCs) contraction (Chiba, 2020) to influence airway remodeling. Moreover, miR-26a induced human airway smooth muscle cells (HASMCs) hypertrophy (Mohamed et al., 2010). MiR-10a reduced mitogen-induced HASMCs proliferation (Hu et al., 2014) to regulate airway remodeling.

MiRNAs are not only the regulators in asthma pathogenesis, but also the targets of asthma therapeutics. Further studies illustrated miRNAs inhibited asthma through downregulation or antagonism of disease-related miRNA (Wang, 2010). Growing evidence showed that up-regulated miRNAs could be inhibited by miRNAs inhibitors or synthetic miRNAs oligonucleotides against miRNAs activity, and the administration of miRNAs inducers that increased tissue-specific miRNAs expression might be another treatment for asthma (Lukiw, 2013; He et al., 2014). For example, miR-155 knockout and miR-106a knockdown alleviated asthma though diminishing airway inflammation, mucus hypersecretion and airway Th2 cytokine levels (Mattes et al., 2009; Huang et al., 2014; Malmhäll et al., 2014). MiRNA-221 blockade suppressed airway inflammation. Moreover, Let-7 miRNA inhibition reduced airway hyperresponsiveness and subepithelial fibrosis by decreasing IL-13 levels to suppress airway inflammation and attenuate mucus metaplasia (Chiba et al., 2009; Kumar et al., 2011) (Table 3).

CircRNAs are a special class of ncRNAs that function as miRNA sponges to indirectly regulate downstream mRNA expression and epigenetically influence various biological processes, especially in cancers (Zhao et al., 2019; Huang et al., 2021b). However, the contribution of circRNAs to childhood asthma progression remains unknown. In recent years, circRNAs have attracted extensive attention in the pathogenesis of childhood asthma.

Huang et al. (2019) showed that circ-0005519 could regulate the secretion of IL-13/IL-6 by competitively sponging let-7a-5p in CD4⁺ T cells from asthma. Previous studies also found that circ-0002594 was a proinflammatory factor in Th2-mediated asthma (Huang et al., 2021b). Circ-0000723 could sponge miR-214 to impact the balance of Th1/Th2 by runt-related transcription factor (RUNX) signal transduction. Moreover, circRNAs also play vital roles in airway smooth muscle cells (ASMCs). Mounting evidence showed that circERBB2 and circHIPK3 could sponge miR-98-5p and miR-326, respectively, and promoted the proliferation of ASMCs by targeting IGF1R and STIM1 (Lin et al., 2020; Huang et al., 2021c). Circ-0001359 could attenuate airway remodeling by targeting FoxO1-dependent M2-like macrophage activation, with sponging miR-183-5p (Shang et al., 2020; Mathis et al., 2021) (Table 4). At present, although there are many studies on the competitively sponging of circRNAs to miRNAs, the specific effect of these circRNAs on asthma is not completely clear. So, the pathogenesis of circRNAs in childhood asthma should be further studied in order to seek for potential diagnostic and therapeutic targets of childhood asthma, which can be used as a new direction of targeted drug therapy.

Although high-dose inhaled corticosteroids and long-acting β2 agonists have been improved for the treatment of asthma, none of these treatments have been shown to alter the natural history of the asthma, and some patients are still failing in these treatments (Sweeney et al., 2012). NcRNAs play an essential role in the treatment and prognosis of asthma. Hence, asthma has been turned to lncRNAs, miRNAs and circRNAs in search of new breakthroughs (Zampetaki et al., 2012; Milagro et al., 2013). Evidences have implicited that lncRNAs, miRNAs and circRNAs can be used as biomarkers of sensitivity and early diagnosis of asthma (Zampetaki et al., 2012). For instance, the expression of lncRNA CASC2 in serum was at a lower level in asthma children than healthy individuals, which suggested that lncRNA CASC2 might be involved in childhood asthma (Yang et al., 2022). Moreover, lnc-BAZ2B also played a crucial role in exacerbating the progression of childhood asthma (Xia et al., 2021). It can be inferred that lncRNA CASC2 and lnc-BAZ2B may serve as potential diagnostic biomarkers, and are expected to become new targets for childhood asthma treatment in the near future. Besides, many surveys have identified that miRNAs such as let-7a, miR-146b-5p, miR-21, miR-532-5p, miR-155 and so on, are promising to be used as diagnostic biomarkers and therapeutic targets in childhood asthma (Kho et al., 2018; Li et al., 2020b; Xu et al., 2020). CircRNAs also play crucial roles to regulate childhood asthma through circRNA-miRNA-mRNA regulatory network and can be served as potential biomarkers and therapeutic targets in childhood asthma (Chen et al., 2021; Wang et al., 2022). Although siRNAs are one of the regulatory ncRNAs, seldom studies have demonstrated the roles of siRNAs in the pathogenesis of childhood asthma. Recently, only several studies have implicated the therapeutic effects of synthetic siRNA in allergen-induced asthma models (Miyamoto et al., 2011; Chen et al., 2017). Consequently, research of drugs related to ncRNAs, especially lncRNAs, miRNAs and circRNAs, may become a new direction in the field of targeted asthma therapy.