Arsenic mobilizes Langerhans cell migration and induces Th1 response in epicutaneous protein sensitization via CCL21: A plausible cause of decreased Langerhans cells in arsenic-induced intraepithelial carcinoma

Arsenic, still a significant environmental threat in several regions in the world, induces various cancers, including lungs, skin, and bladder. Arsenic-induced Bowen's disease (As-BD) is generally an indolent cutaneous intraepithelial carcinoma in susceptible people. Patients with As-BD have been found to have attenuated contact hypersensitivity. Skin samples collected from these patients have reduced numbers of Langerhans cells (LCs), the major epidermal antigen presenting cells expressing Langerins. This study uses an epicutaneous protein sensitization model to investigate the mechanism through which LCs are decreased in As-BD. It further investigates the possibility that arsenic alters LC migration and polarizes Th responses. To do this, we patch-sensitized Balb/c mice or DT-treated Langerin-DTR mice (conditional depletion of Langerin⁺ cells) with OVA or PBS, and fed them water containing 300 ppb arsenic or regular water for 200 μl for five days. Ninety-six hours after OVA sensitization, Langerin⁺EpCAM⁺ cells in arsenic-treated WT mice were significantly increased in draining lymph nodes and decreased in epidermis without changes in the dermis. Lymph node cells from arsenic-treated WT mice were found to proliferate more than lymph node cells from control PBS-treated mice after OVA challenge in vitro. They also secreted more IFN-γ and IL-12, but not IL-4, IL-13, or IL-17. However, cell proliferation and the induction of IFN-γ by arsenic were found to be abolished in DT-treated Langerin-DTR mice. The expressions of CCL21 and CXCL12 were also increased in lymph nodes from arsenic-treated WT mice. The administration of a neutralizing antibody against CCL21, but not CXCL12, abolished the increase of LCs in lymph nodes in vivo. The results of this study, the first to study oral arsenic polarization of Th1 responses in epicutaneous protein sensitization through CCL21-mediated LC migration, suggest the chronicity of As-BD without invasion might result from enhanced Th1 responses and altered LC migrations by arsenic.