Irritant-Induced Migration of Langerhans Cells Coincides with an IL-10-Dependent Switch to a Macrophage-Like Phenotype

Abstract

Langerhans cells (LCs) migrate after topical exposure of the skin to irritants, despite the supposed independence of irritant contact dermatitis from adaptive immunity. Whereas allergen-activated LCs are known to migrate to the draining lymph nodes (LNs), the fate of migrated LCs upon topical irritant exposure is unknown. Here, we identified a phenotypic switch of LCs after their migration into the dermis upon irritant exposure. With the aid of ex vivo intact human skin and epidermal sheets, we show that dermal fibroblasts are necessary for an IL-10-dependent postmigrational phenotypic switch of LCs into macrophage-like cells. Exposure of ex vivo skin to a panel of seven irritants resulted in a decrease in the number of CD1a(+) cells and an increase in CD14(+)/CD68(+) cells in the dermis. Neutralizing antibodies against IL-10 totally inhibited the phenotypic LC-to-macrophage transition, but did not influence the migration of CD1a(+) cells. Exposure of epidermal sheets to irritants resulted in a fibroblast-dependent LC-to-CD14(+)/CD68(+) switch coinciding with migration, which could be totally inhibited by neutralizing antibodies against either IL-10 or CCL2/CCL5 (two chemokines responsible for epidermal-to-dermal migration). We have thus identified an IL-10-dependent phenotypic switch of LCs into macrophage-like cells upon irritant exposure and emigration from the epidermis.

MUTZ-3 Langerhans Cell maturation and CXCL12 independent migration in reconstructed human gingiva

“…This is in line with our previous findings and those of others who reported HLA-DR + DC subsets in human tonsils that lack CD1a expression (Summers et al, 2001;Lundberg et al, 2013), indicating that migration to the draining lymph nodes cannot be ruled out. Most likely the loss of CD1a upon migration is caused by differences in the LP in GE vs. dermis in the SE, consistent with our previous observations that the phenotype of migrating DC is highly plastic and dependent on the cytokine balance in the tissue microenvironment (de Gruijl et al, 2006;Ouwehand et al, 2011a).…”

Intradermal Delivery of TLR Agonists in a Human Explant Skin Model: Preferential Activation of Migratory Dendritic Cells by Polyribosinic-Polyribocytidylic Acid and Peptidoglycans

“…This elevated IL-10 release may also explain why intradermal injection of TLR-Ls, in contrast to GM-CSF plus IL-4, did not reduce the migration frequency of CD14 + DDCs (Fig. 1B), as we previously described IL-10 to skew migratory DCs in skin from a mature to this immature CD14 + phenotype (12,19).…”

Mosquito Saliva Serine Protease Enhances Dissemination of Dengue Virus into the Mammalian Host

“…Proteolysis increases cellular mobility and inflammatory signals within the dermis and enhances interaction between immobilized virions and permissive cell types, such as Langerhans cells or macrophage (29). Irritant and allergen-dependent modulation of the dermal environment has previously been shown to induce migration of Langerhans cells to draining lymph nodes (29)(30)(31)(32). This is correlated with a fibroblast-and IL-10-dependent switch of Langerhans cells to a macrophage-like phenotype and may require the breakdown of integrin-mediated interactions with extracellular matrix components (32,33).…”

“…Irritant and allergen-dependent modulation of the dermal environment has previously been shown to induce migration of Langerhans cells to draining lymph nodes (29)(30)(31)(32). This is correlated with a fibroblast-and IL-10-dependent switch of Langerhans cells to a macrophage-like phenotype and may require the breakdown of integrin-mediated interactions with extracellular matrix components (32,33). In this context, a mosquito serine protease may induce Langerhans cell migration to draining lymph nodes by disrupting interactions between Langerhans cells and the extracellular matrix.…”