Asthma
Asthma is a heterogeneous, chronic disease of the airways associated with airway hyper-reactivity, bronchoconstriction, cough, wheeze and, in the majority of cases, inflammation. The most common and well-studied form of asthma is the allergic type affecting both children and adults. Allergic asthma is marked by increased circulating IgE levels and/or positive skin prick test and triggered by various allergens from pollen and mold to animal dander in addition to airway hyperreactivity. This allergen trigger leads to a cascading type 2 immune response in which type 2 cytokine production, eosinophil numbers and IgE levels are all increased. Given the vast heterogeneity of asthma sub-phenotypes, this section will focus primarily on findings regarding the role of miRNAs in allergic asthma (Table 3 ).
Allergic asthma often begins in early life with up to half of adults reporting asthma symptoms beginning in childhood54. Thus, several studies examined the composition of miRNAs in the circulation and their potential as biomarkers. For example, 122 circulating miRNAs differentiated asthmatic from non-asthmatic children55. The comprehensive inclusion of phenotypic characteristics in the Childhood Asthma Management Program (CAMP) studies allowed the identification of miRNAs that could potentially aid in the treatment of childhood asthma56-58. These miRNAs correlated to lung function parameters after stratification by sex (miR-126, -139, -15b, -186, -342, -374a, -409, -660, -942, male associated and miR-126, -1290, -142, 191, female associated) and to bronchial hyperresponsiveness in response to methacholine challenge (miR-296, -16 and -30d). Applying machine learning to miRNA expression and the clinical score of asthma from the CAMP cohort, these studies suggested a combination of miRNAs as asthma prediction markers (miR-146b, miR-206 and miR-720)58.
In adult asthma, a study identified a set of plasma miRNAs, miR-125b, miR-16, miR-299-, miR-206 and miR-133b, that distinguished asthmatics from healthy individuals and subjects with AR14. let-7a, miR-21, -133a, -155, -328, and -1248 were all found significantly decreased in exhaled breath condensates from asthmatic individuals compared to healthy subjects and predicted target mRNAs indicated numerous type 2 mediators, suggesting a role for these miRNAs in asthma15. miR-21 has been commonly found to be dysregulated in allergic asthma, both in the circulation and in the airways of humans and mice8-10. miRNA expression was also shown to be altered in a temporal manner. When allergic asthmatics were examined in and out of the pollen season, miR-155 was found to be downregulated in lymphocytes from induced sputum only in pollen season, raising the question of which other miRNAs may be altered upon pollen exposure 16. Another prevalent miRNA in asthma, miR-19a has been shown to be a player in asthmatic airways57,59,60. Increased expression of miR-19a in airway T cells promoted type 2 cytokine production through direct targeting of Phosphatase and Tensin Homolog (PTEN) and A20, whereas reduced miR-19a in the airway smooth muscle cells led to enhanced remodeling57,59. In a recent study, decreased epithelial and sputum miR-221 were associated with eosinophilic airway inflammation in asthma61. Even out of the airways, miRNAs have shown potential as predictive markers in asthma. miRNAs from circulating eosinophils, a hallmark in asthma and allergic disease, were examined with miR-185 distinguishing between healthy and asthmatic subjects and showing to be a predictor of asthma severity in blood sera62.
Numerous biomarker studies have been conducted to find both extracellular vesicle derived miRNAs from bronchoalveolar lavage (BAL) and cell-specific miRNAs dysregulated in asthma63-65. Recently more detailed studies have identified potential miRNA targets, suggesting that these aberrant miRNAs alter multiple signaling processes. A negative correlation between lung function parameters and miR-16 in asthma was recently identified. In silico analysis predicted Adrenoreceptor B-2 (ADRB2), which is involved in bronchial smooth muscle contraction, as a target gene for miR-16 and was later confirmed by luciferase assay66. Bioinformatic analysis of miRNA targets from the blood of house dust mite allergic asthmatic children revealed enrichment in the PI3K and NF-κB pathways. More specifically, correlations were shown between their target miRNAs and 3 genes: the E3 ubiquitin ligase CBL, PPARGC1B, which stimulates the activity of various transcription factors and nuclear receptors, and the estrogen receptor ESR1, suggesting that these pathways and genes have a role in asthma pathogenesis67. Additionally, miRNA expression in asthma has been correlated to expression and/or targeting of the type 2 cytokines59,68, IL-13 69and IL-570, as well as VEGF71, key molecules in asthma pathogenesis, strengthening the evidence for their role in the regulation of the disease. Now that the field has a large set of potential miRNAs that are shown to be altered in asthma, it is important for more mechanistic studies to be performed to truly understand their role in asthma pathogenesis.