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Paul S Foster, Maximilian Plank,
Adam Collison,
Hock L Tay,
Gerard E Kaiko,
Jingjing Li,
Sebastian L Johnston,
Philip M Hansbro,
Rakesh K Kumar,
Ming Yang,
Joerg Mattes
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ABSTRACT: Chronic inflammatory diseases of the lung are leading causes of morbidity and mortality worldwide. Many of these disorders can be attributed to abnormal immune responses to environmental stimuli and infections. As such, understanding the innate host defense pathways and their regulatory systems will be critical to developing new approaches to treatment. In this regard, there is increasing interest in the role of microRNAs (miRNAs) in the regulation of pulmonary innate host defense responses and the inflammatory sequelae in respiratory disease. In this review, we discuss recent findings that indicate an important role for miRNAs in the regulation in mouse models of various respiratory diseases and in host defense against bacterial and viral infection. We also discuss the potential utility and limitations of targeting these molecules as anti-inflammatory strategies and also as a means to improve pathogen clearance from the lung.
Immunological Reviews 05/2013; 253(1):198-215. · 11.15 Impact Factor
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ABSTRACT: Glucocorticoids are used as mainstay therapy for asthma, but some patients remain resistant to therapy. MicroRNAs (miRNAs) are important regulators of the immune system by promoting the catabolism of their target transcripts as well as attenuating their translation. The role of miRNA in regulating allergic inflammation remains largely unknown. Blocking miRNA function may provide a new nonsteroidal anti-inflammatory approach to treatment.
To (1) determine the role of specific miRNAs in the regulation of hallmark features of allergic airways inflammation and (2) compare the efficacy of antagonizing miRNA function with that of steroid treatment.
Mice were sensitized and then aeroallergen-challenged with house dust mite to induce allergic airways disease, and alterations in the expression of miRNAs were characterized. Next mice were treated with antagomirs that inhibited the function of specific miRNAs in the lung or treated with dexamethasone and inflammatory lesions, and airway hyperresponsiveness was measured.
miR-145, miR-21, and let-7b have been implicated in airway smooth muscle function, inflammation, and airways epithelial cell function, respectively. Inhibition of miR-145, but not miR-21 or lethal-7b, inhibited eosinophilic inflammation, mucus hypersecretion, T(H)2 cytokine production, and airway hyperresponsiveness. The anti-inflammatory effects of miR-145 antagonism were comparable to steroid treatment.
Our study highlights the importance of understanding the contribution of miRNAs to pathogenesis of human allergic disease and their potential as novel anti-inflammatory targets.
The Journal of allergy and clinical immunology 05/2011; 128(1):160-167.e4. · 9.17 Impact Factor
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ABSTRACT: Allergic asthma is an inflammatory disease of the lung characterized by abnormal T helper-2 (T(H)2) lymphocyte responses to inhaled antigens. The molecular mechanisms leading to the generation of T(H)2 responses remain unclear, although toll-like receptors (TLRs) present on innate immune cells play a pivotal role in sensing molecular patterns and in programming adaptive T cell responses. Here we show that in vivo activation of TLR4 by house dust mite antigens leads to the induction of allergic disease, a process that is associated with expression of a unique subset of small, noncoding microRNAs. Selective blockade of microRNA (miR)-126 suppressed the asthmatic phenotype, resulting in diminished T(H)2 responses, inflammation, airways hyperresponsiveness, eosinophil recruitment, and mucus hypersecretion. miR-126 blockade resulted in augmented expression of POU domain class 2 associating factor 1, which activates the transcription factor PU.1 that alters T(H)2 cell function via negative regulation of GATA3 expression. In summary, this study presents a functional connection between miRNA expression and asthma pathogenesis, and our data suggest that targeting miRNA in the airways may lead to anti-inflammatory treatments for allergic asthma.
Proceedings of the National Academy of Sciences 11/2009; 106(44):18704-9. · 9.68 Impact Factor
