Universität zu Köln

Kumari, Snehlata ORCID: 0000-0002-4971-3162, Preukschat, Daniela, Schuenke, Hannah, Basic, Marijana, Bleich, Andre, Klein, Ulf and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2021). NF-kappa B inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation. Life Sci. Alliance, 4 (6). COLD SPRING HARBOR: LIFE SCIENCE ALLIANCE LLC. ISSN 2575-1077

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kumari, Snehlata UNSPECIFIED orcid.org/0000-0002-4971-3162 UNSPECIFIED Preukschat, Daniela UNSPECIFIED UNSPECIFIED UNSPECIFIED Schuenke, Hannah UNSPECIFIED UNSPECIFIED UNSPECIFIED Basic, Marijana UNSPECIFIED UNSPECIFIED UNSPECIFIED Bleich, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Klein, Ulf UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-584919
DOI:	10.26508/lsa.202000956
Journal or Publication Title:	Life Sci. Alliance
Volume:	4
Number:	6
Date:	2021
Publisher:	LIFE SCIENCE ALLIANCE LLC
Place of Publication:	COLD SPRING HARBOR
ISSN:	2575-1077
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MIXED LINEAGE KINASE; EPITHELIAL-CELL DEATH; DOMAIN-LIKE PROTEIN; INDEPENDENT ROLE; MICE; APOPTOSIS; RIPK3; HOMEOSTASIS; MECHANISMS; EXPRESSION Multiple languages Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58491