Dynamic Changes in Resident and Infiltrating Epidermal Dendritic Cells in Active and Resolved Psoriasis

Abstract

Epidermal Langerhans cells (LCs) are spatially separated from dermal dendritic cells (DCs) in healthy human skin. In active psoriasis, maintained by local production of IL-23 and IL-17, inflammatory DCs infiltrate both skin compartments. Here we show that CCR2 epidermal DCs (eDCs) were confined to lesional psoriasis and phenotypically distinct from dermal DCs. The eDCs exceeded the number of LCs and displayed high expression of genes involved in neutrophil recruitment and the activation of keratinocytes and T cells. Resident LCs responded to toll-like receptor 4 and toll-like receptor 7/8 activation with increased IL-23 production, whereas eDCs additionally produced IL-1β together with IL-23 and tumor necrosis factor. Psoriasis typically recur in fixed skin lesions. eDCs were absent from resolved psoriasis. Instead, LCs from anti-tumor necrosis factor-treated lesions retained high IL23A expression and responded to toll-like receptor stimulation by producing IL-23. Our results reveal phenotypic and functional properties of eDCs and resident LCs in different clinical phases of psoriasis, and the capacity of these cells to amplify the epidermal microenvironment through the secretion of IL-17 polarizing cytokines.

Improved metal allergen reactivity of artificial skin models by integration of Toll‐like receptor 4‐positive cells

“…Our present findings, however, make such a scenario highly unlikely, as neither lesional nor perilesional epidermis obtained from inflamed human skin (ie, from HS patients) expressed substantial amounts of TLR4 mRNA. The lack of substantial TLR4 expression in lesional epidermis was somewhat unexpected, because, at least for psoriasis, increased infiltration of TLR4‐positive DCs has been observed, and epidermal Langerhans cells also express TLR4. However, such DC‐derived TLR4 expression might be obscured by the sheer excess of keratinocytes.…”

Immunological Memory of Psoriatic Lesions

“…On the other hand, colonization of epidermis by eLC, under the influence of TLR-4 and TLR-7/8 activation, produce large amounts of IL-23, and eDCs secrete IL-1β together with IL-23 and TNF-α. After the psoriasis eruption, eDCs are absent in unchanged skin, while eLC retain high IL-23A expression and continue to respond to TLR stimulation, producing IL-23 [47,48]. Although eDCs are 3-10 times more numerous than eLC and drive the psoriatic condition, they also have the ability to produce anti-inflammatory IL-10 [48].…”

“…Their ability to migrate is restored under the influence of treatment (among others anti-TNF, anti-IL-12/23, fumaric acid esters and UVB), except for therapies directed mainly towards T cells (ciclosporin A, MTX) [50][51][52]. Therefore, the observed rapid relapses after discontinuation of ciclosporin A may be explained by the role of LC in the rapid initiation of the inflammation in the same location (effect on TRM expressing IL-23R), which thus affects the memory of psoriatic eruptions [48].…”

Secukinumab treatment in new‐onset psoriasis: aiming to understand the potential for disease modification – rationale and design of the randomized, multicenter STEPIn study

“…Gene expression patterns in skin that appear to be fully resolved from psoriasis after treatment show that subclinical inflammation continues and inflammatory cytokines and chemokines persist . Although the number of inflammatory DCs decreases in resolved lesions, Langerhans cells retain the increased gene expression of IL‐23, thereby contributing to localized disease memories in resolved skin. Skin epithelial stem cells have also been mentioned to serve as memory cells in autoimmune skin disorders .…”