Page 44 - Read Online

Weidner et al. J Transl Genet Genom 2019;3:2. I https://doi.org/10.20517/jtgg.2018.30 Page 9 of 16
[92]
[85]
samples and in the murine allergic model; the previously described miR-223-3p , and miR-21 and a new
[94]
miRNA involved in asthma, miR-27a . Vesicle entrapped miRNAs in both BALF and in exhaled breath
condensates in allergic asthmatics showed decreased expression let-7 family members as well as the miR-
200 family which has been previously shown to regulate epithelial mesenchymal transition and is implicated
[95]
in airway remodeling . Additionally, a recent publication found that miR-200b/c was downregulated in
BALF from young adults, which could be recapitulated in two different mouse models of allergic airway
[96]
inflammation . Furthermore, miR-200b/c was shown to target IL-33 in the airways, suggesting a new
regulator of IL-33 in asthmatic airways.

Neutrophilic asthma
Neutrophilic asthma is debated as a specific phenotype. Neutrophilia is generally seen in corticosteroid-
treated patients and is often associated with severe asthma [81,97] .

[98]
Maes et al. used sputum supernatant from patients with severe asthma, mild-to-moderate asthma,
and healthy subjects. They found three miRNAs, miR-223-3p, -142-3p and -629-3p increased in severe
asthma and associated with neutrophilic airway inflammation. In bronchial biopsies, miR-223-3p, a
miRNA also described to be altered in allergic asthma, was found to be co-localized with neutrophil
elastase positive cells in contact with miR-629-3p expressing epithelial cells. Furthermore, transfection
of primary human bronchial epithelial cells with miR-629-3p mimics generated increased levels of the
neutrophil chemoattractant IL-8 and provided a mechanistic link between increased miR-629-3p and airway
[98]
neutrophilia . In a recent study, miR-199a-5p was found to be increased in plasma and induced sputum
from neutrophilic asthma and negatively correlated to pulmonary function. Peripheral blood derived
neutrophils, lymphocytes and macrophages stimulated by lipopolysaccharide in vitro showed increased miR-
[99]
199a-5p specifically in neutrophils .

Severe asthma
Severe asthma is described as a difficult-to-treat asthma often needing increased medication such as oral
steroids. Neutrophils and/or eosinophilia have been suggested to be a common occurrence, but it is likely
that several subtypes of severe asthma exist [81,97,100] .

Reduced let-7a levels in bronchial biopsies of patients were suggested as a biomarker for severe systemic
glucocorticoid therapy-resistant asthma [101] , but were also found to be reduced in the serum from allergic
[93]
asthmatics . Rupani et al. [102] showed that the expression of toll-like receptor 7 (TLR7) , crucial for
responses to single-stranded RNA viruses, was significantly deficient in alveolar macrophages from severe
asthmatics. TLR7 deficiency in these macrophages was found to be regulated by increased expression of
miR-150, -152, and -375. Furthermore, blocking these miRNAs increased TLR7 expression and restored
IFN responses to virus [102] . Activation of peripheral blood CD8+ T cells correlated with downregulation
of miR-146a/b and miR-28-5p in severe asthmatics [103] . In contrast, airway smooth muscle cells from
asthmatics demonstrated increased expression of miR-146a upon stimulation, which negatively regulated
cyclooxygenase-2 and IL-1b shown by loss of function studies [104] . Another study using airway smooth
muscle cells from severe asthmatics showed increased proliferation and higher IL-6 secretion in response
to TGF-b stimulation compared to cells obtained from mild asthmatics and healthy controls. In addition,
miR-221 was significantly increased in severe asthmatics and inhibition of miR-221 resulted in reduced
proliferation and IL-6 release [105] . Autophagy plays critical roles in airway inflammation and fibrosis-
mediated airway remodeling and many factors including proinflammatory cytokines and inflammation
related pathways are involved in the process. In this study, comprised of plasma samples from asthmatics
ranging from mild to severe, decreased levels of miR-34/449 were shown. In vitro experiments using lung
epithelial cells further showed that miR-34/449 modulated insulin growth factor binding protein-3 mediated
autophagy activation [106] . Interestingly, an earlier study of airway epithelial cells found decreased expression