076 IL-36 signaling is essential for psoriatic inflammation through the augmentation of innate immune responses

Abstract

The IL-1 family member IL-36 consists of 3 agonists and 1 antagonist; IL-36α, IL-36β, and IL-36γ and the receptor antagonist IL-36Ra, respectively. Psoriatic epidermis expresses them except IL-36β. In addition, it has been suggested that the IL-36 pathway plays an important role in innate immunity during psoriasis development, since mice overexpressing IL-36 along with deletion of IL-36Ra gene exhibited a severe psoriatic phenotype. We previously demonstrated that IL-36R KO completely abolished the development of psoriatic inflammation in K5.Stat3C mice. IL-36R is expressed both in epidermal keratinocytes (KCs) and dendritic cells (DCs), both of which likely contribute to psoriatic inflammation. IL-23p40 and TNF-alpha were produced by CD11c+ DCs upon in vitro stimulation with IL-36, however, not by IL-36RKO DCs. Likewise, KCs produced appreciable amounts of IL-17C and IL-36 by in vitro stimulation with IL-36 ligands; however, none of them were produced by IL-36RKO KCs. These results clearly indicated that IL-36R signal in both DCs and KCs has a pivotal role in psoriatic inflammation. To dissect DCs from epidermal keratinocytes regarding role for IL-36R, bone marrow (BM) transplants were conducted in lethally irradiated K5.Stat3C mice. IL-36R+/- mice reconstituted with IL-36RKO BM cells showed more attenuated lesions than IL-36RKO mice transplanted with IL-36R+/-BM reconstitution, suggesting the predominant contribution of IL-36R signal in CD11c+DCs, BM-derived cells, over that in KCs to psoriatic inflammation. Finally, topical treatment with recombinant IL-36Ra successfully attenuated psoriatic skin lesion in K5.Stat3C mice through attenuation of the IL-23/Th17 axis. In addition, IL-36Ra treatment of tissue culture from human psoriatic lesion reduced keratinocyte proliferation and psoriasis-related cytokine levels. In conclusion, IL-36R signal is crucial for the innate immunity of both DCs and KCs in psoriasis development; therefore, IL-36R inhibition would be relevant for a novel therapy for psoriasis.