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Dermal fibroblasts are important relay cells in skin inflammation, highly sensitive to interleukin 1 released by lesioned keratinocytes
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International audience. OBJECTIVE: Keratinocytes are the major source of interleukin 1 (IL-1) which is released after epidermal injury and contributes to trigger sterile skin inflammation. Little is known about the potential target skin cells that express IL-1 receptors and that could act as intermediate cells in the inflammatory process. In this study, we have investigated the capacity of keratinocytes, dermal fibroblasts, melanocytes and endothelial cells to respond to IL-1 in order to identify the main target of IL-1 in the skin.METHODS: The expression profiles of cytokines and receptors of the IL-1 family have been determined by RT-qPCR in the different skin cell populations. Skin cells were stimulated in vitro with keratinocyte extracts or recombinant cytokines of the IL-1 family to measure IL-6 and IL-8 secretion by ELISA. Neutrophil migration assays were performed using these keratinocyte supernatants in the Boyden chamber system. To evaluate the role of IL-1 in vivo, a model of superficial epidermal lesion in wild-type and IL-1R1-deficient mice was used. In mouse lesioned skins, the expression of proinflammatory mediators was analyzed by RT-qPCR and neutrophil infiltration was evaluated by immunohistofluorescence.RESULTS: Among the different skin cells, we show that dermal fibroblasts expressed by far the highest level of the IL-1R1 chain together with the IL-1RAP chain to form the functional receptor that binds both IL-1α and IL-1β. In vitro, fibroblasts are the most responsive skin cells to IL-1α/β released by injured keratinocytes, and secrete high levels of IL-6 and IL-8. Interestingly, we demonstrate that fibroblasts are very sensitive to very low concentrations of IL-1 α/β (from 0.01pg/ml), even in the presence of 100-fold higher concentrations of the antagonist IL-1RA. IL-1-activated fibroblasts have the capacity to attract neutrophils through their release of IL-8 as demonstrated by cell migration assay. Moreover, we show that aseptic epidermal lesion on mouse back induces skin infiltration of neutrophils in an IL-1-dependent manner as demonstrated by the decreased expression of proinflammatory markers and the reduced neutrophil infiltration in the skin of IL-1R1-deficient mice compared to wild-type mice.CONCLUSION: Dermal fibroblasts are the most sensitive cells to IL-1 released by injured keratinocytes after aseptic epidermal lesion by releasing IL-8 and promoting neutrophil recruitment for tissue repair.
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