Mechanism of pathogenesis of imiquimod-induced skin inflammation in the mouse: a role for interferon-alpha in dendritic cell activation by imiquimod

Azumi Ueyama, Mina Yamamoto, Kenichiro Tsujii, Yoko Furue, Chihiro Imura, Michitaka Shichijo, Kiyoshi Yasui
Journal of Dermatology 2014, 41 (2): 135-43
Topical application of imiquimod (IMQ), a Toll-like receptor (TLR)7 ligand, can induce and exacerbate psoriasis, a chronic inflammatory skin disorder. In a mouse model of IMQ-induced psoriasis-like skin inflammation, T-helper (Th)17 cells and interleukin (IL)-17/IL-22-producing γδ-T cells have been shown to play a pivotal role. However, the mechanisms of induction of the Th17 pathway and development of psoriasis-like skin inflammation by IMQ treatment remain unclear. In this study, we investigated pathogenic mechanisms of IMQ-induced psoriasis-like skin inflammation in mice. We first confirmed that, together with an increase in IL-17 and IL-22 production, application of IMQ to mouse skin induced the expression of cytokines required for activation of the Th17 pathway, and pro-inflammatory mediators involved in the pathology of psoriasis. Analysis of Tlr7(-/-) mice demonstrated that most of the in vivo effects of IMQ were mediated via TLR7. In an in vitro study using plasmacytoid dendritic cells (DCs), IMQ induced production of interferon (IFN)-α, IL-23, IL-6 and tumor necrosis factor (TNF)-α. Furthermore, when we analyzed in vitro-generated bone marrow-derived DCs with features similar to TNF-α and inducible nitric oxide synthase (iNOS)-producing DCs, IL-23, IL-6, IL-1β, TNF-α and iNOS/NO production was weakly induced by IMQ alone and further enhanced after co-stimulation with IMQ and IFN-α. These in vitro effects of IMQ were also mediated via TLR7 and the synergistic effect of IMQ, and IFN-α was suggested to be caused by upregulation of TLR7 expression by IFN-α. These results demonstrate part of the mechanism by which the Th17 pathway and psoriasis-like skin inflammation are induced by IMQ and IFN-α in a mouse model.

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