Innate IL-17A Enhances IL-33-independent Skin Eosinophilia and IgE Response on Subcutaneous Papain Sensitization

IL-33-activated group 2 innate lymphoid cells critically contribute to protease allergen-induced airway inflammation models. However, IL-33 is dispensable for a subcutaneous papain-induced skin inflammation model, suggesting distinct mechanisms between intranasal and subcutaneous sensitization. We herein examined the role of IL-17A in the subcutaneous model. Papain-exposed skin produced IL-17A and an excess amount of a soluble decoy receptor for IL-33, with the latter being a possible reason for the independence of the subcutaneous model from IL-33. An IL-17A deficiency attenuated papain-induced skin eosinophilia and serum papain-specific IgE/IgG1 levels, while the subcutaneous administration of IL-17A with enzymatically inactive papain enhanced serum papain-specific IgE/IgG1 levels and Th2 development in draining lymph nodes (DLNs) in an IL-33-independent manner, suggesting IL-33-independent enhancement of papain-specific type 2 responses by IL-17A. Subcutaneous papain increased IL-17A⁺ γδ T cells in DLNs, approximately half of which were Vγ4⁺, as the majority of IL-17A⁺ cells, and increased Vγ5⁺ and Vγ4⁺ γδ T cells in skin. Depletion of γδ TCR⁺ cells reduced Th cytokine production in antigen-restimulated DLN cells. These results suggest a novel role for IL-17A as an enhancer of skin eosinophilia and serum antigen-specific IgE production, and for γδ T cells as an enhancer of Th cell activation in the subcutaneous papain model.

Keywords: IL-17A; Murine model; Papain; Subcutaneous administration; soluble ST2; γδ T cells.