PT - JOURNAL ARTICLE AU - Sina Webering AU - Lars Lunding AU - Heinz Fehrenbach AU - Michael Wegmann TI - LSC 2014 abstract - RORγ t-specific RNAi decreases allergic airway inflammation and airway hyperresponsiveness in a mouse model of neutrophilic asthma DP - 2014 Sep 01 TA - European Respiratory Journal PG - 1719 VI - 44 IP - Suppl 58 4099 - http://erj.ersjournals.com/content/44/Suppl_58/1719.short 4100 - http://erj.ersjournals.com/content/44/Suppl_58/1719.full SO - Eur Respir J2014 Sep 01; 44 AB - Introduction: Recent studies suggest T helper 17 (Th17) cells as important players in the progression of asthma towards a severe phenotype. Regulated by the transcription factor Retinoic acid-related Orphan Receptor gamma (RORγ) t, which is essential for the differentiation of these cells, Th17 cells appear to act as general promoters of chronic inflammatory responses. Thus, it is conceivable to make use of this transcription factor as a prime target for therapeutic intervention.Therefore, the aim of this study was to diminish RORγ t expression by usingsmall interfering RNAs(siRNAs) and to characterize its effects on Th17 cell activity in-vitro and in-vivo.Methods: Th17 cells were generated in-vitro and transfected with several siRNA candidates targeting RORγ t. Afterwards, the in-vivo relevance of siRNA-mediated downregulation of RORγ t was characterized in a mouse model of neutrophilic asthma.Results: SiRNA-transfected Th17 cells revealed not only reduced expression of RORγ t but also of proinflammatory cytokines such as IL-17A. Intratracheal application of the most active siRNA in a mouse model of neutrophilic asthma inhibited the development of airway hyperresponsiveness to methacholine. In addition, application of the RORγ t-specific siRNA prevented airway inflammation characterized by a significantly reduced number of neutrophils and decreased bronchoalveolar lavage IL17A, TNF-α and KC levels.Conclusion: Our data show that knockdown of RORγ t by gene silencing improved airway inflammation in a mouse model of experimental asthma and may have therapeutic potential for the treatment of neutrophilic asthma.