MicroRNAs in inflammatory lung disease--master regulators or target practice?

Abstract

MicroRNAs (miRNAs) have emerged as a class of regulatory RNAs with immense significance in numerous biological processes. When aberrantly expressed miRNAs have been shown to play a role in the pathogenesis of several disease states. Extensive research has explored miRNA involvement in the development and fate of immune cells and in both the innate and adaptive immune responses whereby strong evidence links miRNA expression to signalling pathways and receptors with critical roles in the inflammatory response such as NF-κB and the toll-like receptors, respectively. Recent studies have revealed that unique miRNA expression profiles exist in inflammatory lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis and lung cancer. Evaluation of the global expression of miRNAs provides a unique opportunity to identify important target gene sets regulating susceptibility and response to infection and treatment, and control of inflammation in chronic airway disorders. Over 800 human miRNAs have been discovered to date, however the biological function of the majority remains to be uncovered. Understanding the role that miRNAs play in the modulation of gene expression leading to sustained chronic pulmonary inflammation is important for the development of new therapies which focus on prevention of disease progression rather than symptom relief. Here we discuss the current understanding of miRNA involvement in innate immunity, specifically in LPS/TLR4 signalling and in the progression of the chronic inflammatory lung diseases cystic fibrosis, COPD and asthma. miRNA in lung cancer and IPF are also reviewed.

Figure 1

Representation of miRNA induction and biogenesis. Induction of miRNA expression occurs via transcription factors and other regulatory influences. Primary miRNA transcripts (pri-miRNA) produced in the nucleus are generally processed by Drosha and DGCR8 into pre-miRNA hairpin structures and transported to the cytoplasm by Exportin 5. The pre-miRNA is processed by Dicer into a miRNA duplex where the mature miRNA guide strand is incorporated into a miRNA-induced silencing complex (miRISC) and the miRNA* strand is degraded. Incorporation into miRISC is facilitated by AGO proteins. Importin 8 aids subsequent transport of the miRNA to the target mRNA where binding to the 3'UTR occurs resulting in translational repression or degradation.

Figure 2

Selection of miRNA implicated in the TLR4 signalling pathway. TLR4 signals via MyD88 and TIRAP/MAL to IRAKs 1 and 4. The TOM1/Tollip complex and SOCS1 are negative regulators of this pathway. The signal is transduced via TRAF6, TAK1 and IKK leading to activation of NF-κB via dissociation of IκB. κB-Ras2B is an IκB inhibitor. miRNA targeting components of TLR4 signalling are shown in boxes. MiR-145 [126].