RT Journal Article
SR Electronic
T1 NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202000956
DO 10.26508/lsa.202000956
VO 4
IS 6
A1 Snehlata Kumari
A1 Trieu-My Van
A1 Daniela Preukschat
A1 Hannah Schuenke
A1 Marijana Basic
A1 André Bleich
A1 Ulf Klein
A1 Manolis Pasparakis
YR 2021
UL https://www.life-science-alliance.org/content/4/6/e202000956.abstract
AB 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.