title: Tumor necrosis factor receptor signaling in keratinocytes triggers interleukin-24-dependent psoriasis-like skin inflammation in mice.
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.
authors.affiliation: 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.
authors.forename: Snehlata
authors.initials: S
authors.lastname: Kumari
authors.forename: Marion C
authors.initials: MC
authors.lastname: Bonnet
authors.forename: Maria H
authors.initials: MH
authors.lastname: Ulvmar
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wolk
authors.forename: Niki
authors.initials: N
authors.lastname: Karagianni
authors.forename: Ellen
authors.initials: E
authors.lastname: Witte
authors.forename: Claudia
authors.initials: C
authors.lastname: Uthoff-Hachenberg
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
authors.forename: George
authors.initials: G
authors.lastname: Kollias
authors.forename: Rune
authors.initials: R
authors.lastname: Toftgard
authors.forename: Robert
authors.initials: R
authors.lastname: Sabat
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.forename: Ingo
authors.initials: I
authors.lastname: Haase
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004817:Epidermis / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency / Q000502:physiology; D007378:Interleukins / Q000502:physiology; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D011565:Psoriasis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018123:Receptors, Interleukin / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D000099180:Interleukin-24
chemical_list: D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D051550:I-kappa B Kinase; D007378:Interleukins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D018123:Receptors, Interleukin; D047888:Receptors, Tumor Necrosis Factor, Type I; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D000099180:Interleukin-24; C431904:Il24 protein, mouse; C494087:Stat3 protein, mouse; C506236:Tnfrsf1a protein, mouse; C415369:interleukin-22 receptor; C496562:Ikbkb protein, mouse