The role of IL-33 cytokine in allergic sensitization and inflammation

Abstract

In this study, we sought to understand the role of interleukin-33 (IL-33) in the context of allergic sensitization and inflammation. To achieve this, we developed two novel models of IL-33 driven allergic sensitization and inflammation. Genetically modified mouse strains with cell specific IL-33 receptor knockouts, hyperactivating receptor variants, and cytokine knock outs were used to characterize these models and determine important responding cell types. Using an intradermal sensitization model with IL-33 and ovalbumin on WT C57BL/6 mice, we observed an increase in draining lymph node cellularity, antigen-specific IgE titers, and Th2 cell generation within skin-draining lymph nodes demonstrating evidence of classic allergic sensitization. Using CD4 T and dendritic cell specific ST2 deficient mouse lines we found that direct IL-33/ST2 signaling on CD4 T cell is necessary for a complete type 2 response. Without this signaling, we found an overall dampened type 2 sensitization response with a significant reduction in total effector Th2 cells and IgE titer. Our findings also suggest a possible role of CD11c+ dendritic cells in responding to IL-33 as we found an increased overall frequency of type 2-skewed CD4 T cells. To expand on our sensitization protocol we included several multi-day oral challenges with ovalbumin to induce antigen dependent eosinophil-rich allergic inflammation within the esophagus of mice. This established an IL-33 driven model of eosinophilic esophagitis (EoE). In characterizing the model we measured esophageal eosinophilia levels over a 7 day time course with a peak occurring after 7x challenges. We also determined that the model was antigen specific and IL-5 dependent. We also found that mice carrying a hyperactive ST2 SNP, rs10204137, showed no difference in eosinophilia levels. Collectively, these studies underscore the significance of IL-33 in promoting allergic sensitization, with CD4 T cells identified as a critical responding cell type in skin-draining lymph nodes, alongside the establishment of an IL-33 driven model for EoE.