| First Author | Kumari S | Year | 2021 |
| Journal | Life Sci Alliance | Volume | 4 |
| Issue | 6 | PubMed ID | 33858959 |
| Mgi Jnum | J:320988 | Mgi Id | MGI:6729560 |
| Doi | 10.26508/lsa.202000956 | Citation | Kumari S, et al. (2021) NF-kappaB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation. Life Sci Alliance 4(6) |
| abstractText | Tumor necrosis factor receptor 1 (TNFR1) activates NF-kappaB-dependent pro-inflammatory gene expression, but also induces cell death by triggering apoptosis and necroptosis. Inhibition of inhibitor of NF-kappaB kinase (IKK)/NF-kappaB 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-kappaB 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-kappaB-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. |
