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

Oglesby IK, McElvaney NG, Greene CM - Respir. Res. (2010)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.

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.

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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].
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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].

Mentions: Of the TLRs characterised to date, TLR4 in particular has been the subject of the majority of studies where a firm link between miRNA expression and TLR4 signalling pathways is now recognised, (depicted in Figure 2). The vast majority of studies have been performed in macrophages (murine and human, in vitro and in vivo) and to a lesser extent, neutrophils, PBMCs and epithelial cells. LPS, one of the major ligands for TLR4 has been associated with induction of several miRNA including miR-155, -146, -9 and -21 to name a few, which were shown to target SHIP1, IRAK1/TRAF6, NF-κB1, and tumor suppressor PDCD4 respectively [54-57]. Expression of miR-155 can also be induced by additional TLR ligands and a plethora of pro-inflammatory cytokines [53] and in the context of inflammatory lung disease mice deficient in miR-155 display immunodeficiency and substantial airway remodelling [43]. Notably, the position of the Bic/miR-155 gene in humans is located on chromosome 21q21 mapping to a region of asthma and pollen sensitivity [58,59]. Up-regulation of miR-9 expression shown to occur upon treatment with TLR2, 4, 7 and 8 agonists, IL-1β and TNF-α but not IFNγ was the only miRNA found to be differentially expressed in both human neutrophils and monocytes following stimulation with LPS [54].


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

Oglesby IK, McElvaney NG, Greene CM - Respir. Res. (2010)

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].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2984500&req=5

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].
Mentions: Of the TLRs characterised to date, TLR4 in particular has been the subject of the majority of studies where a firm link between miRNA expression and TLR4 signalling pathways is now recognised, (depicted in Figure 2). The vast majority of studies have been performed in macrophages (murine and human, in vitro and in vivo) and to a lesser extent, neutrophils, PBMCs and epithelial cells. LPS, one of the major ligands for TLR4 has been associated with induction of several miRNA including miR-155, -146, -9 and -21 to name a few, which were shown to target SHIP1, IRAK1/TRAF6, NF-κB1, and tumor suppressor PDCD4 respectively [54-57]. Expression of miR-155 can also be induced by additional TLR ligands and a plethora of pro-inflammatory cytokines [53] and in the context of inflammatory lung disease mice deficient in miR-155 display immunodeficiency and substantial airway remodelling [43]. Notably, the position of the Bic/miR-155 gene in humans is located on chromosome 21q21 mapping to a region of asthma and pollen sensitivity [58,59]. Up-regulation of miR-9 expression shown to occur upon treatment with TLR2, 4, 7 and 8 agonists, IL-1β and TNF-α but not IFNγ was the only miRNA found to be differentially expressed in both human neutrophils and monocytes following stimulation with LPS [54].

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.

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.

Show MeSH
Related in: MedlinePlus