IL-4 acts on skin-derived dendritic cells to promote the TH2 response to cutaneous sensitization and the development of allergic skin inflammation

Background: Atopic dermatitis is characterized by scratching and a TH2-dominated local and systemic response to cutaneously encountered antigens. Dendritic cells (DCs) capture antigens in the skin and rapidly migrate to draining lymph nodes (dLNs) where they drive the differentiation of antigenObjective: We sought to determine whether non-T-cell-derived IL-4 acts on skin-derived DCs to promote the TH2 response to cutaneously encountered antigen and allergic skin inflammation. Methods: DCs from dLNs of ovalbumin (OVA)-exposed skin were analyzed by flow cytometry and for their ability to polarize OVA-specific naive CD41 T cells. Skin inflammation following epicutaneous sensitization of tape-stripped skin was assessed by flow cytometry of skin cells and real-time quantitative PCR of cytokines. Cytokine secretion and antibody levels were evaluated by ELISA. Results: Scratching upregulated IL4 expression in human skin. Similarly, tape stripping caused rapid basophil-dependent upregulation of cutaneous Il4 expression in mouse skin. In vitro treatment of DCs from skin dLNs with IL-4 promoted their capacity to drive TH2 differentiation. DCs from dLNs of OVAsensitized skin of Il4-/- mice and CD11c-CreIl4rflox/-mice, which lack IL-4Ra expression in DCs (DC degrees/degrees ll4ra mice), were impaired in their capacity to drive TH2 polarization compared with DCs from controls. Importantly, OVA-sensitized DC degrees/degrees ll4ra mice demonstrated impaired allergic skin inflammation and OVA-specific systemic TH2 response evidenced by reduced TH2 cytokine secretion by OVA-stimulated splenocytes and lower levels of OVA-specific IgE and IgG1 antibodies, compared with controls. Conclusions: Mechanical skin injury causes basophildependent upregulation of cutaneous IL-4. IL-4 acts on skin DCs that capture antigen and migrate to dLNs to promote their capacity for TH2 polarization and drive allergic skin inflammation.