Distinct migration behaviors of monocyte-derived versus resident langerhans cells drive the pathogenesis of imiquimod-induced skin inflammation.

BACKGROUND: Langerhans cells (LCs) consist of embryonically derived resident LCs (rLCs) and monocyte-derived LCs (moLCs), yet how distinct LC subsets migrate and function during psoriatic skin inflammation remains incompletely understood. OBJECTIVE: To characterize the migratory behavior and immunological roles of rLCs and moLCs in imiquimod (IMQ)-induced skin inflammation. METHODS: We examined LC subset dynamics in an IMQ-induced murine dermatitis model using flow cytometry and immunofluorescence. To dissect subset-specific functions, moLCs were selectively ablated in Cd207fl/flLyz2Cre conditional knockout mice, while rLCs were depleted using Langerin-DTR mice. Skin inflammation severity, T cell profiles, and PD-L1 expression were assessed. Human psoriatic lesions (mild vs. moderate-to-severe) were analyzed by multiplex immunofluorescence. RESULTS: IMQ treatment induced progressive moLC accumulation in skin lesions (both number and proportion increased), while rLCs diminished locally but accumulated significantly in draining lymph nodes with upregulated CCR7 expression. Genetic ablation of moLCs reduced epidermal hyperplasia, ear thickness, and IL-17/IL-22-producing CD4+ T cells and γδ T cells in lesions. Conversely, rLC depletion exacerbated dermatitis, reduced PD-L1 expression in lymph node LCs, and enhanced γδ T cell activation both locally and systemically. In human psoriatic lesions, moLC density correlated with local lesion severity at the histological level, while CCR7 expression was predominantly detected on rLCs rather than moLCs. CONCLUSION: rLCs and moLCs display distinct migratory behaviors and exert divergent immunological functions during IMQ-induced skin inflammation. Lesion-retained moLCs are associated with local inflammatory responses, whereas lymph node-migratory rLCs are linked to immunoregulatory activity.