Long Noncoding RNAs in the Regulation of Asthma: Current Research and Clinical Implications

Abstract

Asthma is a chronic airway inflammatory disorder related to variable expiratory airflow limitation, leading to wheeze, shortness of breath, chest tightness, and cough. Its characteristic features include airway inflammation, airway remodeling and airway hyperresponsiveness. The pathogenesis of asthma remains extremely complicated and the detailed mechanisms are not clarified. Long noncoding RNAs (lncRNAs) have been reported to play a prominent role in asthma and function as modulators of various aspects in pathological progress of asthma. Here, we summarize recent advances of lncRNAs in asthma pathogenesis to guide future researches, clinical treatment and drug development, including their regulatory functions in the T helper (Th) 1/Th2 imbalance, Th17/T regulatory (Treg) imbalance, eosinophils dysfunction, macrophage polarization, airway smooth muscle cells proliferation, and glucocorticoid insensitivity.

Keywords: airway inflammation; airway remodeling; asthma; glucocorticoid insensitivity; long noncoding RNAs.

Figure 1

The mechanism of miRs. MicroRNAs (MiRs) are bond with argonaute proteins (Ago), Dicer and trans-activation response RNA-binding protein (TRBP) to form the RNA-induced silencing complex (RISC). In the case of incomplete complementary sequences, they bind to mRNA to translation inhibition. In the case of complete complementary sequences, they bind to 3’ untranslated regions (UTR) of mRNA to mRNA degradation. Besides, they can bind to transcription factors to coregulate the transcription of genes.

Figure 2

The mechanism of lncRNAs. Long noncoding RNAs (lncRNAs) direct bind to the genes to translation inhibition, splicing modification, and mRNA degradation. Alternatively, they act as a competitive endogenous RNA (ceRNA) that has the microRNA (miR) response element to sponge the miR to further prevent mRNA degradation and enhance the mRNA expression. lncRNAs also mediate chromatin remodeling for chromatin modification and function as an RNA decoy that binds to the transcription factors to regulate the downstream signaling pathways. They assemble ribonucleoprotein (RNP) complexes to modulate protein stability as well.

Figure 3

The influence of downregulated and upregulated lncRNAs in asthma pathogenesis. Blue indicates the inhibition function and red indicates the promotion function. According to the current studies of asthma, seven long noncoding RNAs (lncRNAs) are upregulated and two lncRNAs are downregulated in T helper (Th) 1/Th2 imbalance. lncRNA MEG3 is upregulated in Th17/T regulatory (Treg) imbalance. In addition, lncRNA RP11-401.2 is upregulated in EOS dysfunction and seven lncRNAs are upregulated in airway smooth muscle cells (ASMCs) proliferation. However, previous studies have not yet found the downregulated lncRNAs in Th17/Treg imbalance, EOS dysfunction or ASMCs proliferation. lncRNA AK085865 and lnc-BAZ2B are upregulated whereas lncRNA PTPRE-AS1 is downregulated in macrophage polarization. On the aspect of glucocorticoid insensitivity in asthma, lncRNA growth arrest-special transcript 5 (GAS5) is upregulated whereas cancer susceptibility candidate 7 (CASC7) and lncRNA plasmacytoma variant translocation (PVT1) (nonsevere asthma) are downregulated.