Langerin neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Mice, Knockout 1000 Multidisciplinary EMC MM-02-72-02 0303 health sciences Imiquimod Membrane Glycoproteins EMC MM-03-61-05-A 610 Medicine & health 10263 Institute of Experimental Immunology Interleukin-23 3. Good health Disease Models, Animal Mice 03 medical and health sciences Mannose-Binding Lectins Toll-Like Receptor 7 Langerhans Cells Antigens, Surface Myeloid Differentiation Factor 88 Aminoquinolines 570 Life sciences; biology Animals Psoriasis Lectins, C-Type
DOI: 10.1073/pnas.1307569110 Publication Date: 2013-06-11T04:02:47Z
ABSTRACT
Psoriasis is an autoinflammatory skin disease of unknown etiology. Topical application of Aldara cream containing the Toll-like receptor (TLR)7 agonist Imiquimod (IMQ) onto patients induces flares of psoriasis. Likewise, in mice IMQ triggers pathological changes closely resembling psoriatic plaque formation. Key cytokines like IL-23 and type-I IFN (IFN-I), both being produced mainly by dendritic cells (DCs), have been implicated in psoriasis. Although plasmacytoid DCs (pDCs) are the main source of IFNα and thought to initiate disease, conventional DCs (cDCs) appear to maintain the psoriatic lesions. Any role of cDCs during lesion formation remains elusive. Here, we report that selective activation of TLR7 signaling specifically in CD11c + DCs was sufficient to induce psoriasiform skin disease in mice. Intriguingly, both pDCs and the IFN-I pathway were dispensable for the development of local skin inflammation. Selective TLR7 triggering of Langerin + DCs resulted in attenuated disease, whereas their depletion did not alter the severity of skin lesions. Moreover, after IMQ-painting, IL-23 was exclusively produced by Langerin neg DCs in vivo. In conclusion, TLR7-activated Langerin neg cDCs trigger psoriatic plaque formation via IL-23–mediated activation of innate IL-17/IL-22–producing lymphocytes, independently of pDCs or IFN-I. These results suggest therapeutic targeting of IL-23 production by cDCs to refine current treatment strategies for psoriasis.
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