Epidermal Structure and Barrier Function| Volume 138, ISSUE 5, SUPPLEMENT , S116, May 2018

685 Necroptosis as special type of cell death in inflammatory skin diseases

      Epithelial structure and homeostasis of the skin depend on the balance between cell survival and cell death. In inflammatory skin diseases (ISD) cell death mechanisms are often dysregulated. This study shows an important role of receptor-interacting protein kinase-3 (RIP3)-regulated necroptosis - one type of regulated necrosis - in keratinocytes besides apoptosis. We detected a significantly enhanced epidermal expression of RIP3 in lichen planus (LP) and lupus erythematosus (LE) in comparison to healthy and psoriasis skin biopsies. Additionally, the analysis of T cells from lesional LE and LP skin biopsies revealed a dominant type I immune response with high frequencies of IFN-γ and TNF-α positive cells. These findings indicated a role of IFN-γ and TNF-α in the induction of RIP3 and initiation of necroptosis. In vitro we showed that either IFN-γ or TNF-α but not IFN-α induced the production of RIP3 in keratinocytes and lead to cell swelling and vacuolization of keratinocytes in three-dimensional skin equivalents. Interestingly, shRNA knockdown of RIP3 prevented necroptosis of keratinocytes. Thus, necroptosis and RIP3 in particular represent potential targets for treatment of ISD like LE and LP.