Atopic dermatitis (AD) is a pruritic inflammatory skin disease that affects> 15% of children (Bieber, 2008). Acute AD skin lesions are characterized by epidermal and dermal thickening and by dermal infiltration of CD4+ T cells and eosinophils, as well as predominant expression of the Th2 cytokines IL-4 and IL-13; expression of IL-22 is also significantly (Homey e t al., 2006) elevated in AD skin lesions (Nograles et al., 2009; Khattri et al., 2014). A hallmark of AD is a dry itchy skin with a disrupted barrier function, which is caused in a large number of patients by filaggrin deficiency (Morar et al., 2007). Mechanical skin injury caused by scratching aggravates the defect in skin barrier function and leads to the release of cytokines that play key roles in driving the immune response to cutaneously encountered antigens (Homey et al., 2006). Epicutaneous (EC) sensitization with allergens plays an important role in the pathogenesis of AD (Kubo et al., 2012). Approximately 80% of patients with AD are sensitized to allergens, as indicated by elevated serum total IgE levels with specific IgE antibodies to environmental allergens (Leung, 2000). Importantly, application of allergens to the abraded uninvolved skin of patients with AD provokes an eczematous rash with characteristics of acute AD skin lesions (Mitchell et al., 1982). IL-22 is a member of the IL-10 family of cytokines produced by adaptive Th17 and Th22 cells, innate lymphocytes that include γδ T cells and type 3 innate lymphoid cells (ILC3), and myeloid cells, including neutrophils (Xie et al., 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.