Abstract
Several subtypes of APCs are found in psoriasis patients, but their involvement in disease pathogenesis is poorly understood. Here, we investigated the contribution of Langerhans cells (LCs) and plasmacytoid DCs (pDCs) in psoriasis. In human psoriatic lesions and in a psoriasis mouse model (DKO* mice), LCs are severely reduced, whereas pDCs are increased. Depletion of pDCs in DKO* mice prior to psoriasis induction resulted in a milder phenotype, whereas depletion during active disease had no effect. In contrast, while depletion of Langerin-expressing APCs before disease onset had no effect, depletion from diseased mice aggravated psoriasis symptoms. Disease aggravation was due to the absence of LCs, but not other Langerin-expressing APCs. LCs derived from DKO* mice produced increased IL-10 levels, suggesting an immunosuppressive function. Moreover, IL-23 production was high in psoriatic mice and further increased in the absence of LCs. Conversely, pDC depletion resulted in reduced IL-23 production, and therapeutic inhibition of IL-23R signaling ameliorated disease symptoms. Therefore, LCs have an anti-inflammatory role during active psoriatic disease, while pDCs exert an instigatory function during disease initiation.
Highlights
Psoriasis is a frequent pathology of the skin affecting about 2% of the total Western population
Contrary to what was observed for Langerhans cells (LCs), the number of plasmacytoid dendritic cells (DCs) (pDCs) was significantly increased within lesional skin (Fig 1D and E), where pDCs accumulated predominantly in the papillary dermis, in line with what was previously reported for human psoriasis (Wollenberg et al, 2002)
Two studies suggested that a dermal DC subset may be involved in psoriasis initiation via the production of IL-23 (Wohn et al, 2013), a key cytokine that mediates expansion of IL-17- and IL-22-producing cells, promoting important events in psoriasis pathology, including neutrophil infiltration and epidermal thickening (Di Cesare et al, 2009)
Summary
Psoriasis is a frequent pathology of the skin affecting about 2% of the total Western population. It is characterized by inflamed lesions that display abnormal keratinocyte proliferation and differentiation as well as prominent immune cell infiltration. Both the innate and the adaptive immune system play a role in the pathomechanism of psoriasis (Nestle et al, 2009), and several cues point to a role of keratinocytes in psoriasis etiology (Nickoloff, 2006). IL-23 promotes the maintenance of T cells producing IL-17 and IL-22, which are abundant in and contribute to many of the hallmarks seen in psoriasis In psoriatic skin, these are constituted by both CD4+ and CD8+ TCRab+ T cells, as well as cd T cells, and the recently discovered innate lymphoid cells (ILCs) (Dyring-Andersen et al, 2014; Lowes et al, 2014)
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