TY - JOUR T1 - NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202000956 VL - 4 IS - 6 SP - e202000956 AU - Snehlata Kumari AU - Trieu-My Van AU - Daniela Preukschat AU - Hannah Schuenke AU - Marijana Basic AU - André Bleich AU - Ulf Klein AU - Manolis Pasparakis Y1 - 2021/06/01 UR - https://www.life-science-alliance.org/content/4/6/e202000956.abstract N2 - Tumor necrosis factor receptor 1 (TNFR1) activates NF-κB–dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-κB kinase (IKK)/NF-κB signaling in keratinocytes paradoxically unleashed spontaneous TNFR1-mediated skin inflammation in mice, but the underlying mechanisms remain poorly understood. Here, we show that TNFR1 causes skin inflammation in mice with epidermis-specific knockout of IKK2 by inducing receptor interacting protein kinase 1 (RIPK1)–dependent necroptosis, and to a lesser extent also apoptosis, of keratinocytes. Combined epidermis-specific ablation of the NF-κB subunits RelA and c-Rel also caused skin inflammation by inducing TNFR1-mediated keratinocyte necroptosis. Contrary to the currently established model that inhibition of NF-κB–dependent gene transcription causes RIPK1-independent cell death, keratinocyte necroptosis, and skin inflammation in mice with epidermis-specific RelA and c-Rel deficiency also depended on RIPK1 kinase activity. These results advance our understanding of the mechanisms regulating TNFR1-induced cell death and identify RIPK1-mediated necroptosis as a potent driver of skin inflammation. ER -