NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation.
Animals
Apoptosis
/ physiology
Female
I-kappa B Kinase
/ metabolism
Inflammation
/ metabolism
Keratinocytes
/ metabolism
Male
Mice
Mice, Knockout
NF-kappa B
/ metabolism
Necroptosis
/ genetics
Receptor-Interacting Protein Serine-Threonine Kinases
/ genetics
Receptors, Tumor Necrosis Factor, Type I
/ metabolism
Signal Transduction
Skin
/ metabolism
Tumor Necrosis Factor-alpha
/ pharmacology
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
13
11
2020
revised:
01
04
2021
accepted:
01
04
2021
entrez:
16
4
2021
pubmed:
17
4
2021
medline:
13
10
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33858959
pii: 4/6/e202000956
doi: 10.26508/lsa.202000956
pmc: PMC8091601
pii:
doi:
Substances chimiques
NF-kappa B
0
Receptors, Tumor Necrosis Factor, Type I
0
Tnfrsf1a protein, mouse
0
Tumor Necrosis Factor-alpha
0
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
Ripk1 protein, mouse
EC 2.7.11.1
I-kappa B Kinase
EC 2.7.11.10
Ikbkb protein, mouse
EC 2.7.11.10
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2021 Kumari et al.
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