Metabolic mechanisms underlying IL-33 mediated Th2 polarization and allergic airway disease (IRM7P.494)

Abstract

Abstract IL-33 is a recent IL-1 cytokine with emerging pleotropic functions. Experimental studies have suggested that IL-33 supports Treg responses, drives CD8+ T cell IFN-γ production, and acts as a potent mediator of Th2 responses. The current study tests the hypothesis that IL-33 modulates mDC gene expression and pathway activities facilitating Th2 polarization. Using gene expression and efficiency analysis, we identified multiple genes involved in iron homeostasis and metabolism which were upregulated in mDC by IL-33. Desferrioxamine (DFO) was utilized to assess the impact of blocking mDC iron uptake during IL-33 stimulation on subsequent Th2 polarization and capacity to stimuli allergic airway disease (AAD). Generation of CD4+IL-5+ Th2 cells by IL-33-exposed DC was ablated by iron chelation, resulting in decreased IL-5 production and cellular proliferation. However, induced Th1 responses were unaffected in DFO-treated LPS-stimulated DC. Using an OVA/IL-33 mDC induced model of AAD, blocking DC iron uptake with DFO decreased several phenotypic hallmarks of the disease, including IgE (p<0.05) and IL-33 production in the lungs of animals. In conclusion, iron uptake is necessary for IL-33 generation of pro-inflammatory DC supporting Th2 polarization. Blocking iron uptake in a model of mDC induced AAD alters disease phenotype when compared to control animals. These data suggest that regulation of iron uptake may be a potential mechanism behind IL-33 induction of Th2 responses.