Epidermis-to-dermis migration of immature Langerhans cells upon topical irritant exposure is dependent on CCL2 and CCL5

Skin irritation is generally not considered to be an immunological event; however, alterations in the density of Langerhans cells (LC) in the epidermis do occur, which is indicative of LC migration. In this study, we investigated the migration of LC out of the epidermis after skin exposure to contact irritants and identified the chemokines involved. With the aid of ex vivo-intact human skin and epidermal sheets we show that dermal fibroblasts play a role in mediating LC migration towards the dermis. Exposure of ex vivo-intact human skin to a panel of seven irritants (SDS, salicylic acid, phenol, isopropanol, DMSO, TritonX, or benzalkonium chloride) resulted in decreased numbers of CD1a(+) cells in the epidermis and the accumulation of CD1a(+) cells in the dermis. In contrast to allergen exposure, neutralizing antibodies to either CXCL12 or CCL19/CCL21 did not inhibit LC migration out of the epidermis. Exposure of epidermal sheets to the prototypical irritant SDS resulted in a TNF-alpha-dependent LC migration towards dermal fibroblasts. This was a result of CCL2/MCP-1 and CCL5/RANTES chemokine secretion by fibroblasts: injection of CCL2- and CCL5-neutralizing antibodies into intact human skin totally inhibited LC migration into the dermis. We have thus identified a novel role for TNF-alpha-inducible dermis-derived CCL2 and CCL5 in initiating migration of irritant-exposed human LC out of the epidermis.