Critical role of caspase-8-mediated IL-1 signaling in promoting Th2 responses during asthma pathogenesis

Allergic asthma is a chronic inflammatory disorder of the airways that affects 4300 million people worldwide. The pro-inflammatory cytokines interleukin (IL)-1 alpha and IL-1 beta have essential roles in the pathogenesis of asthma. However, the mechanisms underlying the production of IL-1 cytokines in allergic asthma remain unclear. In this study, we used a mouse model of ovalbumin-induced asthma to identify a crucial role for caspase-8 in the development of allergic airway inflammation. We further demonstrated that hematopoietic cells have dominant roles in caspase-8-mediated allergic airway inflammation. Caspase-8 was required for the production of IL-1 cytokines to promote Th2 immune response, which promotes the development of pulmonary eosinophilia and inflammation. Thus, our study identifies caspase-8 as a master regulator of IL-1 cytokines that contribute to the pathogenesis of asthma and implicates caspase-8 inhibition as a potential therapeutic strategy for asthmatic patients.