Tumor necrosis factor receptor signaling in keratinocytes triggers interleukin-24-dependent psoriasis-like skin inflammation in mice

Snehlata Kumari; Marion C Bonnet; Maria H Ulvmar; Kerstin Wolk; Niki Karagianni; Ellen Witte; Claudia Uthoff-Hachenberg; Jean-Christophe Renauld; George Kollias; Rune Toftgard; Robert Sabat; Manolis Pasparakis; Ingo Haase

doi:10.1016/j.immuni.2013.10.009

Tumor necrosis factor receptor signaling in keratinocytes triggers interleukin-24-dependent psoriasis-like skin inflammation in mice

Immunity. 2013 Nov 14;39(5):899-911. doi: 10.1016/j.immuni.2013.10.009. Epub 2013 Nov 7.

Authors

Snehlata Kumari¹, Marion C Bonnet, Maria H Ulvmar, Kerstin Wolk, Niki Karagianni, Ellen Witte, Claudia Uthoff-Hachenberg, Jean-Christophe Renauld, George Kollias, Rune Toftgard, Robert Sabat, Manolis Pasparakis, Ingo Haase

Affiliation

¹ Department of Dermatology, University of Cologne, Kerpener Strasse 62, 50931 Cologne, Germany; Institute for Genetics, Center for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47a, 50674 Cologne, Germany.

PMID: 24211183
DOI: 10.1016/j.immuni.2013.10.009

Abstract

Psoriasis is a common chronic inflammatory skin disease with a prevalence of about 2% in the Caucasian population. Tumor necrosis factor (TNF) plays an essential role in the pathogenesis of psoriasis, but its mechanism of action remains poorly understood. Here we report that the development of psoriasis-like skin inflammation in mice with epidermis-specific inhibition of the transcription factor NF-κB was triggered by TNF receptor 1 (TNFR1)-dependent upregulation of interleukin-24 (IL-24) and activation of signal transducer and activator of transcription 3 (STAT3) signaling in keratinocytes. IL-24 was strongly expressed in human psoriatic epidermis, and pharmacological inhibition of NF-κB increased IL-24 expression in TNF-stimulated human primary keratinocytes, suggesting that this mechanism is relevant for human psoriasis. Therefore, our results expand current views on psoriasis pathogenesis by revealing a new keratinocyte-intrinsic mechanism that links TNFR1, NF-κB, ERK, IL-24, IL-22R1, and STAT3 signaling to disease initiation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
Crosses, Genetic
Cytokines / biosynthesis
Cytokines / genetics
Cytokines / physiology*
Disease Models, Animal
Epidermis / pathology
Gene Expression Regulation / physiology
Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis
Humans
I-kappa B Kinase / deficiency
I-kappa B Kinase / physiology
Interleukins / physiology
Keratinocytes / metabolism
Keratinocytes / pathology*
MAP Kinase Signaling System
Mice
Mice, Knockout
Mice, Transgenic
NF-kappa B / metabolism
Psoriasis / etiology*
Psoriasis / pathology
Psoriasis / physiopathology
Reactive Oxygen Species / metabolism
Receptors, Interleukin / physiology
Receptors, Tumor Necrosis Factor, Type I / deficiency
Receptors, Tumor Necrosis Factor, Type I / genetics
Receptors, Tumor Necrosis Factor, Type I / physiology*
STAT3 Transcription Factor / physiology
Tumor Necrosis Factor-alpha / antagonists & inhibitors
Tumor Necrosis Factor-alpha / physiology*

Substances

Cytokines
Il24 protein, mouse
Interleukins
NF-kappa B
Reactive Oxygen Species
Receptors, Interleukin
Receptors, Tumor Necrosis Factor, Type I
STAT3 Transcription Factor
Stat3 protein, mouse
Tnfrsf1a protein, mouse
Tumor Necrosis Factor-alpha
interleukin-22 receptor
interleukin-24
Granulocyte-Macrophage Colony-Stimulating Factor
I-kappa B Kinase
Ikbkb protein, mouse