Increasing Filamins A and B in Th2 Lymphocytes as a Therapeutic Opportunity to Attenuate Airway Inflammation in Mice

Background. Nearly half of asthmatic patients present a high type 2 inflammation initiated by the release of type 2 cytokines in the lungs. Th2 lymphocytes represent a major source of these cytokines and are key drivers of asthma pathogenesis. The ASB2α ubiquitin ligase is a positive regulator of Th2 lymphocyte functions that triggers degradation of filamins A and B (FLNa/b) leading to effective cell migration. Accordingly, loss of ASB2α in Th2 lymphocytes reduces their recruitment in inflamed lungs and attenuates airway inflammation in preclinical models of asthma. Here, we asked whether increasing FLNa/b levels in Th2 lymphocytes with pharmacological agents may represent a therapeutic opportunity to attenuate type 2 inflammation. Methods. A functional screen of library compounds was performed to identify small molecules that cause increased FLNa/b levels in ASB2α-expressing cells. In vitro experiments including immunological techniques and live imaging were used to investigate the effects of such hits in mouse primary Th2 lymphocytes. In vivo mouse models of airway inflammation and airway hyperreactivity were used to investigate the impact of these hits on type 2 inflammation. Results. The assay we developed led to the identification of two compounds, thiostrepton and oxibendazole, that reduce the dynamic migratory behavior of Th2 lymphocytes, and attenuate type 2 inflammation and airway hyperresponsiveness in mouse models of allergic airway inflammation. Conclusions. Our results show that augmenting FLNa/b levels in Th2 lymphocytes improves features of asthma, reinforcing the view that ASB2α and its substrates FLNa/b may represent novel pharmacological targets in type 2 pathologies.