NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation.
Life Sci Alliance
; 4(6)2021 06.
Article
in En
| MEDLINE
| ID: mdl-33858959
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Keratinocytes
/
Receptor-Interacting Protein Serine-Threonine Kinases
/
Necroptosis
Type of study:
Etiology_studies
/
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Life Sci Alliance
Year:
2021
Document type:
Article
Affiliation country: