NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation

Tumor necrosis factor receptor 1 (TNFR1) activates NF-kappa B-dependent pro- inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-kappa B kinase (IKK)/NF-kappa B 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-kappa B 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-kappa B-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.

Automated summary

Research reveals that TNFR1 induces keratinocyte necroptosis and skin inflammation in mice with epidermis-specific IKK2 knockout, as well as similar results in mice with epidermis-specific RelA and c-Rel deficiency. RIPK1-mediated necroptosis is identified as a potent driver of skin inflammation.