IL-23 induced in keratinocytes by endogenous TLR4 ligands polarizes dendritic cells to drive IL-22 responses to skin immunization.

Juhan Yoon, Juan Manuel Leyva-Castillo, Guoxing Wang, Claire Galand, Michiko K Oyoshi, Lalit Kumar, Sabine Hoff, Rui He, Alexander Chervonsky, Joost J Oppenheim, Vijay K Kuchroo, Marcel R M van den Brink, Rene De Waal Malefyt, Philippe A Tessier, Robert Fuhlbrigge, Philip Rosenstiel, Cox Terhorst, George Murphy, Raif S Geha
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The journal of experimental medicine
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Atopic dermatitis (AD) is a Th2-dominated inflammatory skin disease characterized by epidermal thickening. Serum levels of IL-22, a cytokine known to induce keratinocyte proliferation, are elevated in AD, and Th22 cells infiltrate AD skin lesions. We show that application of antigen to mouse skin subjected to tape stripping, a surrogate for scratching, induces an IL-22 response that drives epidermal hyperplasia and keratinocyte proliferation in a mouse model of skin inflammation that shares many features of AD. DC-derived IL-23 is known to act on CD4(+) T cells to induce IL-22 production. However, the mechanisms that drive IL-23 production by skin DCs in response to cutaneous sensitization are not well understood. We demonstrate that IL-23 released by keratinocytes in response to endogenous TLR4 ligands causes skin DCs, which selectively express IL-23R, to up-regulate their endogenous IL-23 production and drive an IL-22 response in naive CD4(+) T cells that mediates epidermal thickening. We also show that IL-23 is released in human skin after scratching and polarizes human skin DCs to drive an IL-22 response, supporting the utility of IL-23 and IL-22 blockade in AD.