The iron sequestering protein Lipocalin 2 is critical to IL-33-exposed dendritic cell stimulation of Th2 responses and allergic airway disease (IRC7P.424)

Abstract IL-33 is an IL-1 cytokine with emerging pleotropic functions, but ascribed a prominent role in Type 2-mediated responses to pathogens due to its capacity to generate and support T helper type 2 (Th2) cells. Likewise, IL-33 and Th2 cell are viewed as dominant drivers of inflammatory lung disorders, including asthma. Previous studies have revealed that IL-33 stimulates the capacity of dendritic cells (DC) to initiate Th2 responses and, thus instigate allergic airway disease (AAD) in mice. However, the precise mechanisms by which IL-33 promotes DC-mediated Th2 polarization was not known. To answer this question, we preformed microarray analysis on DC after exposure to IL-33. This analysis identified multiple genes involved in iron homeostasis and metabolism upregulated by IL-33. The most dramatically increase gene in DC by IL-33 was Lipocalin 2 (Lcn2), an iron sequestering protein that facilitates DC iron uptake. After IL-33-exposure, DC deficient in Lcn2 displayed a significantly reduced capacity to generate Th2 responses, however, LPS-exposed DC lacking Lcn2 were fully capable of Th1 polarization. Identical finding were observed when DC iron uptake was blocked through chelation during their exposure to IL-33. In a DC-induced model of AAD, blocking DC iron uptake resulted in significantly decreased disease severity. These data define a novel role for IL-33-stimulated iron uptake by Lcn2 in the generation of Th2 responses.