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.
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.
Joerg
J
Mattes
Adam
A
Collison
Maximilian
M
Plank
Simon
S
Phipps
Paul S
PS
Foster
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