miRNAs in the regulation of virus-induced asthma exacerbation
Viruses affecting the respiratory system, such as human rhinoviruses (RVs), respiratory syncytial virus (RSV) and influenza, are known to cause serious illness and exacerbation in asthma patients72-74. When infecting human bronchial epithelial cells (HBECs), these viruses activate the NF-κB pathway and interferon signaling in order to induce cellular responses, restrict virus replication and avoid tissue damage. It has been suggested that HBECs of asthmatic patients might have weakened interferon responses, resulting in increased viral propagation, enhanced activation of NF-κB and immune responses and asthma exacerbations75. In this context, it can be envisioned that miRNAs targeting the NF-κB pathway and influencing interferon singnaling may have great potential to modulate cellular responses to respiratory viruses and influence the exacerbation of asthma. Accordingly, one of the earliest studies addressing the question of miRNA involvement in the regulation of viral responses showed an increase in viral replication of RV-1B in HBECs when DICER was knocked down and, additionally, miR-128 and -155 were inhibited76. Another study found that miR-18a, -27a, -128 and -155 were downregulated in asthmatic HBECs and that simultaneous knockdown of these four miRNAs led to a significant increase in IL-8 and IL-6 expression77. Differences in the bronchial epithelium of asthmatic patients may also occur due to epigenetic changes78. miRNAs can influence genes involved in epigenetic regulation or modification and may also influence cellular responses to respiratory viruses. Indeed, a recent study demonstrated the upregulation of miR-22 and downregulation of its target genes histone deacetylase (HDAC)4 and CD147 in response to influenza A virus H1N1 in bronchial epithelial cells from healthy subjects. However, cells from asthmatic patients were incapable of upregulating miR-22 and showed increased and unchanged levels of HDAC4 and CD147, respectively79. Several additional studies suggest important functions for miRNAs in the regulation of cellular and immune responses to respiratory viruses (Table 4 ). One example are three miRNAs from different families (miR-24, -124a, -744) that all interfere with the p38 MAPK pathway, through the downstream kinases MK2 and Myc. MK2 and Myc are essential pro-viral host factors and their downregulation by these miRNAs (or small interfering RNA (siRNAs)) confers broad-spectrum antiviral activity against influenza A virus, RSV and adenovirus80. Most studies, however, are performed in immortalized bronchial epithelial cells and rarely utilize primary respiratory epithelial cultures, clinical samples or in vivo mouse models. Thus, information about the real role of miRNAs in respiratory viral infections and virus-induced asthma exacerbations remains very limited.