Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease.
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.
Mattes
Joerg
J
Faculty of Health, School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, John Hunter Children's Hospital, Callaghan, NSW 2300, Australia.
Collison
Adam
A
Plank
Maximilian
M
Phipps
Simon
S
Foster
Paul S
PS
D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000150:complications / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D020868:Gene Silencing; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000150:complications / Q000235:genetics / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000276:immunology
D039741:Antigens, Dermatophagoides; C545201:MIRN126 microRNA, mouse; D035683:MicroRNAs; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4