Normal epidermal differentiation but impaired skin-barrier formation upon keratinocyte-restricted IKK1 ablation

Gareus, Ralph; Huth, Marion; Breiden, Bernadette; Nenci, Arianna; Rösch, Nora; Haase, Ingo; Bloch, Wilhelm; Sandhoff, Konrad; Pasparakis, Manolis

doi:10.1038/ncb1560

Cited by 88 publications

(93 citation statements)

References 35 publications

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“…In suprabasal keratinocytes of the epidermis, IKK␣ mediates repression of the members of the fibroblast growth factor family, a process independent of the intact kinase activity (56). IKK␣ has also been implicated in the control of the skin-barrier formation through the regulation of the retinoic acid receptor target genes in keratinocytes (53). An important role in keratinocyte differentiation has also been proposed for IKK␤.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, NF-B was found to play an important role in the physiology of keratinocytes, and disruption or modulation of components of the NF-B signaling affected epidermal proliferation, differentiation, and homeostasis (28,41,(53)(54)(55)(56)(57). Consequently, the terminal differentiation of keratinocytes was perturbed in the absence of proper activation of NF-B (57) primarily because of the lack of IKK␣-dependent expression of a differentiation-inducing factor (57).…”

Section: Discussionmentioning

confidence: 99%

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Targeting NF-κB with a Natural Triterpenoid Alleviates Skin Inflammation in a Mouse Model of Psoriasis

Wang

Syrovets

Keß

et al. 2009

The Journal of Immunology

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Psoriasis vulgaris is a common chronic inflammatory skin disease involving cytokines and an activated cellular immune system. At variance to skin from patients with atopic dermatitis or from healthy subjects, human psoriatic skin lesions exhibit strong activation of transcription factor NF-κB that is mainly confined to dermal macrophages, whereas only a few dendritic cells but no CD3+ lymphocytes show activated NF-κB. Since NF-κB signaling is required for the induction and/or function of many cytokines and aberrant cytokine expression has been proposed as an underlying cause of psoriasis, we investigated whether NF-κB targeting would affect the course of the disease in the CD18 hypomorphic (CD18hypo) mouse model of psoriasis. When mice with severe psoriasiform lesions were treated systemically or locally with the IκB kinase inhibitor acetyl-11-keto-β-boswellic acid (AKβBA), NF-κB signaling and the subsequent NF-κB-dependent cytokine production as shown by the TNF-α production of macrophages were profoundly suppressed. Additionally, application of the compound counteracted the intradermal MCP-1, IL-12, and IL-23 expression in previously lesional skin areas, led to resolution of the abundant immune cell infiltrates, and significantly reduced the increased proliferation of the keratinocytes. Overall, the AKβBA treatment was accompanied by a profound improvement of the psoriasis disease activity score in the CD18hypo mice with reconstitution of a nearly normal phenotype within the chosen observation period. Our data demonstrate that NF-κB signaling is pivotal for the pathogenesis in the CD18hypo mouse model of psoriasis. Therefore, targeting NF-κB might provide an effective strategy for the treatment of psoriasis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting NF-κB with a Natural Triterpenoid Alleviates Skin Inflammation in a Mouse Model of Psoriasis

Wang

Syrovets

Keß

et al. 2009

The Journal of Immunology

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“…Partial keratinocyte differentiation in vivo, but in the absence of differentiation in vitro, was also observed for IKK1 − / − skin. [32][33][34][35] However, the molecular mechanism explaining the difference between these in vivo and in vitro data remains elusive.…”

Section: G H and I)mentioning

confidence: 99%

A novel RIPK4–IRF6 connection is required to prevent epithelial fusions characteristic for popliteal pterygium syndromes

et al. 2014

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Receptor-interacting protein kinase 4 (RIPK4)-deficient mice have epidermal defects and fusion of all external orifices. These are similar to Bartsocas-Papas syndrome and popliteal pterygium syndrome (PPS) in humans, for which causative mutations have been documented in the RIPK4 and IRF6 (interferon regulatory factor 6) gene, respectively. Although genetically distinct, these syndromes share the anomalies of marked pterygia, syndactyly, clefting and hypoplastic genitalia. Despite the strong resemblance of these two syndromes, no molecular connection between the transcription factor IRF6 and the kinase RIPK4 was known and the mechanism underlying the phenotype was unclear. Here we describe that RIPK4 deficiency in mice causes epithelial fusions associated with abnormal periderm development and aberrant ectopic localization of E-cadherin on the apical membrane of the outer peridermal cell layers. In Xenopus, RIPK4 depletion causes the absence of ectodermal epiboly and concomitant gastrulation defects that phenocopy ectopic expression of dominant-negative IRF6. We found that IRF6 controls RIPK4 expression and that wild-type, but not kinase-dead, RIPK4 can complement the gastrulation defect in Xenopus caused by IRF6 malfunctioning. In contrast to the mouse, we observed only minor effects on cadherin membrane expression in Xenopus RIPK4 morphants. However, gastrulation defects were associated with a virtual absence of cortical actin in the ectodermal cells that face the blastocoel cavity and this was phenocopied in embryos expressing dominant-negative IRF6. A role for RIPK4 in actin cytoskeleton organization was also revealed in mouse epidermis and in human epithelial HaCaT cells. In conclusion, we showed that in mice RIPK4 is implicated in cortical actin organization and in E-cadherin localization or function, which can explain the characteristic epithelial fusions observed in PPSs. In addition, we provide a novel molecular link between IRF6 and RIPK4 that unifies the different PPSs to a common molecular pathway.

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“…C57BL/6, baff-r Ϫ/Ϫ (5), ikk1 f/f (29), mb1-cre (30) and E -Bcl2 (31) mice were bred and maintained in specific pathogen free conditions. All mouse protocols were approved by the Harvard University and the Immune Disease Institute Institutional Animal Care and Use Committees.…”

Section: Methodsmentioning

confidence: 99%

BAFF activates Akt and Erk through BAFF-R in an IKK1-dependent manner in primary mouse B cells

Otipoby

Sasaki

Schmidt-Supprian

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Normal epidermal differentiation but impaired skin-barrier formation upon keratinocyte-restricted IKK1 ablation

Cited by 88 publications

References 35 publications

Targeting NF-κB with a Natural Triterpenoid Alleviates Skin Inflammation in a Mouse Model of Psoriasis

Targeting NF-κB with a Natural Triterpenoid Alleviates Skin Inflammation in a Mouse Model of Psoriasis

A novel RIPK4–IRF6 connection is required to prevent epithelial fusions characteristic for popliteal pterygium syndromes

BAFF activates Akt and Erk through BAFF-R in an IKK1-dependent manner in primary mouse B cells

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