Emerging Roles of Non-Coding RNAs in Childhood Asthma

Abstract

Asthma is a chronic airway inflammatory disease in children characterized by airway inflammation, airway hyperresponsiveness and airway remodeling. Childhood asthma is usually associated with allergy and atopy, unlike adult asthma, which is commonly associated with obesity, smoking, etc. The pathogenesis and diagnosis of childhood asthma also remains more challenging than adult asthma, such as many diseases showing similar symptoms may coexist and be confused with asthma. In terms of the treatment, although most childhood asthma can potentially be self-managed and controlled with drugs, approximately 5-10% of children suffer from severe uncontrolled asthma, which carries significant health and socioeconomic burdens. Therefore, it is necessary to explore the pathogenesis of childhood asthma from a new perspective. Studies have revealed that non-coding RNAs (ncRNAs) are involved in the regulation of respiratory diseases. In addition, altered expression of ncRNAs in blood, and in condensate of sputum or exhalation affects the progression of asthma via regulating immune response. In this review, we outline the regulation and pathogenesis of asthma and summarize the role of ncRNAs in childhood asthma. We also hold promise that ncRNAs may be used for the development of biomarkers and support a new therapeutic strategy for childhood asthma.

Keywords: childhood asthma; circRNAs; lncRNAs; miRNAs; ncRNAs.

FIGURE 1

Childhood asthma and adult asthma phenotypes. Childhood asthma and adult asthma are crossed and different in phenotypes. In children, Th2-type asthma is the main common type. Allergen stimulates the recruitment of inflammatory cells such as eosinophils, the proliferation and activation of immune cells such as mast cells and DCs, and induces the injury of airway epithelial cells, which lead to the release of inflammatory factors and Th2 cytokines, such as IL4, IL5 and IL13. In adult, both Th2-type and non-Th2-type asthma are two common types. Upon pollutants stimulation, type I innate lymphoid cells (ILC1) and type III innate lymphoid cells activation (ILC3) activate neutrophils and airway epithelial cells to drive the proliferation of Th17 cells which mediates in turn neutrophil recruitment. Pollutants also contribute to M1 macrophage and NK cell recruitment to the airways, resulting in non-Th2-type asthma in adult.

FIGURE 2

Immunopathogenesis of Th2-type asthma. 1) Under IL-4 induction, dendritic 2 (DC2) cell promotes the development of Th0 cells to Th2, resulting in Th1 (decreased secretion)/Th2 (increased secretion) cell dysfunction. 2) Upon stimulation by allergens, bronchial epithelial cells release IL-25, IL-33 and TSLP, which in turn activates group II innate lymphoid cells (ILC2) and Th2 cells. 3) Subsequently, Th2 cells release Th2 cytokines such as IL-4, IL-5 and IL-13, rather than Th1 cells produce IFN-γ and TNF-β, causing a balanced skewed Th2 cellular immune response. 4) IgE eventually induces rapid onset allergy and cytokines release induced by eosinophils, mast cells and other immune cells, leading to airway inflammation. 5) Moreover, different miRNAs have different effects on the above processes. The red boxes in the picture show typical miRNAs that exert upregulated function in asthma. The blue boxes show miRNAs that exert downregulated function.

FIGURE 3

Roles of various MAPK signaling pathways in asthmatic pathogenesis. ERK favors Th2 cell differentiation, eosinophils priming, degranulation, cytokine and leukotriene production, mast cells proliferation/differentiation. The p38 MAPKs and JNK pathways regulate Th1 differentiation. The p38 MAPK contributes to eosinophil degranulation, migration and cytokine production and mast cell migration. The JNK participates in cytokine production by mast cells, regulates the proliferation of B cell, and exerts function in asthmatic pathogenesis.