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Berlin Brandenburg

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  • Keratinocytes
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  • 1
    Language: English
    In: The Journal of clinical investigation, November 2012, Vol.122(11), pp.3965-76
    Description: Psoriasis is a chronic inflammatory disorder of the skin affecting approximately 2% of the world's population. Accumulating evidence has revealed that the IL-23/IL-17/IL-22 pathway is key for development of skin immunopathology. However, the role of keratinocytes and their crosstalk with immune cells at the onset of disease remains poorly understood. Here, we show that IL-36R-deficient (Il36r-/-) mice were protected from imiquimod-induced expansion of dermal IL-17-producing γδ T cells and psoriasiform dermatitis. Furthermore, IL-36R antagonist-deficient (Il36rn-/-) mice showed exacerbated pathology. TLR7 ligation on DCs induced IL-36-mediated crosstalk with keratinocytes and dermal mesenchymal cells that was crucial for control of the pathological IL-23/IL-17/IL-22 axis and disease development. Notably, mice lacking IL-23, IL-17, or IL-22 were less well protected from disease compared with Il36r-/- mice, indicating an additional distinct activity of IL-36 beyond induction of the pathological IL-23 axis. Moreover, while the absence of IL-1R1 prevented neutrophil infiltration, it did not protect from acanthosis and hyperkeratosis, demonstrating that neutrophils are dispensable for disease manifestation. These results highlight a central and unique IL-1-independent role for IL-36 in control of the IL-23/IL-17/IL-22 pathway and development of psoriasiform dermatitis.
    Keywords: Cell Communication -- Immunology ; Dendritic Cells -- Immunology ; Dermatitis -- Immunology ; Interleukin-1 -- Immunology ; Keratinocytes -- Immunology ; Psoriasis -- Immunology
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 2
    Language: English
    In: Free Radical Biology and Medicine, November 2015, Vol.88, pp.243-252
    Description: The skin is frequently exposed to environmental challenges, such as UV irradiation, toxic chemicals, and mechanical wounding. These insults cause an increase in the levels of reactive oxygen species, resulting in oxidative stress and concomitant inflammation, skin aging, and even cancer development. Therefore, an efficient antioxidant defense strategy is of major importance in this tissue. Since the Nrf2 transcription factor regulates a battery of genes involved in the defense against reactive oxygen species and in compound metabolism, it plays a key role in skin homeostasis, repair, and disease. In this review we summarize current knowledge on the expression and function of Nrf2 in normal skin and its role in the acute and chronic UV response as well as in the pathogenesis of epithelial skin cancer and of different inflammatory skin diseases. Finally, we discuss the potential of Nrf2-activating compounds for skin protection under stress conditions and for the treatment of major human skin disorders.
    Keywords: Nrf2 ; Oxidative Stress ; Skin Cancer ; Wound Healing ; Inflammation ; Chemoprevention ; Biology ; Anatomy & Physiology
    ISSN: 0891-5849
    E-ISSN: 1873-4596
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  • 3
    Language: English
    In: Developmental Cell, 11 December 2012, Vol.23(6), pp.1238-1246
    Description: The loss of loricrin, a major component of the cornified envelope, results in a delay of epidermal barrier formation. Therefore, the living layers of the epidermis are aberrantly exposed to late-stage amniotic fluid, which may serve as the signal to upregulate genes that functionally compensate for the loss of loricrin. Consistent with this hypothesis, metabolomic studies revealed marked changes in amniotic fluid between E14.5 and E16.5 days postcoitum. In addition, we discovered that the Nrf2/Keap1 pathway detects these compositional changes and directly upregulates the expression of genes involved in the compensatory response, thus ensuring postnatal survival. In support of this finding, we demonstrate that genetically blocking the Nrf2 pathway abolishes the compensatory response and that preemptively activating Nrf2 pharmacologically rescues the delay in barrier formation in utero. Our findings reveal that the functions of Nrf2 and the composition of amniotic fluid have coevolved to ensure the formation of a functional barrier. ► Nrf2-activating metabolites are present in late-stage amniotic fluid ► and are direct downstream targets of Nrf2 in the epidermis ► Blocking the Nrf2 pathway in the loricrin null mouse results in postnatal lethality ► Pharmacological activation of Nrf2 in utero rescues the delay in barrier formation Mutations in epidermal differentiation genes often cause a developmental delay in epidermal barrier formation, which must be resolved before birth to ensure survival. Huebner et al. discover that aberrant in utero exposure of keratinocytes to late-stage amniotic fluid activates the Nrf2/Keap1 pathway, and this compensatory mechanism rescues barrier formation.
    Keywords: Biology
    ISSN: 1534-5807
    E-ISSN: 1878-1551
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  • 4
    Language: English
    In: EMBO Molecular Medicine, May 2012, Vol.4(5), pp.364-379
    Description: The skin provides an efficient permeability barrier and protects from microbial invasion and oxidative stress. Here, we show that these essential functions are linked through the Nrf2 transcription factor. To test the hypothesis that activation of Nrf2 provides skin protection under stress conditions, we determined the consequences of pharmacological or genetic activation of Nrf2 in keratinocytes. Surprisingly, mice with enhanced Nrf2 activity in keratinocytes developed epidermal thickening, hyperkeratosis and inflammation resembling lamellar ichthyosis. This resulted from upregulation of the cornified envelope proteins small proline‐rich proteins (Sprr) 2d and 2h and of secretory leukocyte peptidase inhibitor (Slpi), which we identified as novel Nrf2 targets in keratinocytes. Since Sprrs are potent scavengers of reactive oxygen species and since Slpi has antimicrobial activities, their upregulation contributes to Nrf2's protective function. However, it also caused corneocyte fragility and impaired desquamation, followed by alterations in the epidermal lipid barrier, inflammation and overexpression of mitogens that induced keratinocyte hyperproliferation. These results identify an unexpected role of Nrf2 in epidermal barrier function, which needs to be considered for pharmacological use of Nrf2 activators. →See accompanying article
    Keywords: Barrier Function ; Inflammation ; Nrf2 ; Oxidative Stress ; Skin
    ISSN: 1757-4676
    E-ISSN: 1757-4684
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  • 5
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 01 June 2016, Vol.196(11), pp.4663-70
    Description: The Nrf2 transcription factor is well known for its cytoprotective functions through regulation of genes involved in the detoxification of reactive oxygen species or toxic compounds. Therefore, activation of Nrf2 is a promising strategy for the protection of tissues from various types of insults and for cancer prevention. However, recent studies revealed a proinflammatory activity of activated Nrf2 and a stimulating effect on epithelial cell proliferation, but the underlying mechanisms of action and the responsible target genes are largely unknown. Using a combination of gene expression profiling, chromatin immunoprecipitation, and targeted proteomics via selected reaction monitoring, we show that the gene encoding the proinflammatory cytokine IL-36γ is a novel direct target of Nrf2 in keratinocytes and hepatocytes in vitro and in vivo. As a consequence, upregulation of IL-36γ expression occurred upon genetic or pharmacological activation of Nrf2 in the epidermis and in the normal and regenerating liver. Functional in vitro studies demonstrate that IL-36γ directly stimulates proliferation of keratinocytes. In particular, it induces expression of keratinocyte mitogens in fibroblasts, suggesting that the Nrf2-IL-36γ axis promotes keratinocyte proliferation through a double paracrine loop. These results provide mechanistic insight into Nrf2 action in the control of inflammation and cell proliferation through regulation of a proinflammatory cytokine with a key function in various inflammatory diseases.
    Keywords: Autocrine Communication ; Cell Proliferation ; Paracrine Communication ; Interleukin-1 -- Metabolism ; Keratinocytes -- Cytology ; Nf-E2-Related Factor 2 -- Metabolism
    E-ISSN: 1550-6606
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 6
    In: Cell Death and Differentiation, 2018, Vol.25(10), p.1749-1765
    Description: The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of the cellular stress response, but the biological functions of the related Nrf3 protein are largely unknown. Here we demonstrate a novel pro-apoptotic function of Nrf3 in mouse and human keratinocytes....
    Keywords: Article ; Cell Adhesion ; Experimental Models Of Disease
    ISSN: 1350-9047
    E-ISSN: 1476-5403
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  • 7
    Language: English
    In: Genes & development, 15 May 2010, Vol.24(10), pp.1045-58
    Description: Ultraviolet (UV) B irradiation can severely damage the skin and even induce tumorigenesis. It exerts its effects by direct DNA modification and by formation of reactive oxygen species (ROS). We developed a strategy to genetically activate target gene expression of the transcription factor NF-E2-related factor 2 (Nrf2) in keratinocytes in vivo based on expression of a constitutively active Nrf2 mutant. Activation of Nrf2 target genes strongly reduced UVB cytotoxicity through enhancement of ROS detoxification. Remarkably, the protective effect was extended to neighboring cells. Using different combinations of genetically modified mice, we demonstrate that Nrf2 activates the production, recycling, and release of glutathione and cysteine by suprabasal keratinocytes, resulting in protection of basal cells in a paracrine, glutathione/cysteine-dependent manner. Most importantly, we found that endogenous Nrf2 controls selective protection of suprabasal keratinocytes from UVB-induced apoptosis through activation of cytoprotective genes. This finding explains the preferential UVB-induced apoptosis of basal cells, which is important for elimination of mutated stem cells as well as for preservation of skin integrity. Taken together, our results identify Nrf2 as a key regulator in the UV response of the skin.
    Keywords: Ultraviolet Rays ; Cytoprotection -- Physiology ; Glutathione -- Metabolism ; Keratinocytes -- Metabolism ; Nf-E2-Related Factor 2 -- Genetics
    ISSN: 08909369
    E-ISSN: 1549-5477
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  • 8
    In: Nature Communications, 2014, Vol.5
    Description: The Nrf2 transcription factor controls the expression of genes involved in the antioxidant defense system. Here, we identified Nrf2 as a novel regulator of desmosomes in the epidermis through the regulation of microRNAs. On Nrf2 activation, expression of miR-29a and miR-29b increases in cultured human keratinocytes and in mouse epidermis. Chromatin immunoprecipitation identified the Mir29ab1 and Mir29b2c genes as direct Nrf2 targets in keratinocytes. While binding of Nrf2 to the Mir29ab1 gene activates expression of miR-29a and -b, the Mir29b2c gene is silenced by DNA methylation. We identified desmocollin-2 (Dsc2) as a major target of Nrf2-induced miR-29s. This is functionally important, since Nrf2 activation in keratinocytes of transgenic mice causes structural alterations of epidermal desmosomes. Furthermore, the overexpression of miR-29a/b or knockdown of Dsc2 impairs the formation of hyper-adhesive desmosomes in keratinocytes, whereas Dsc2 overexpression has the opposite effect. These results demonstrate that a novel Nrf2-miR-29-Dsc2 axis controls desmosome function and cutaneous homeostasis.
    Keywords: Biology;
    ISSN: 2041-1723
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  • 9
    Language: English
    In: The Journal of biological chemistry, 21 September 2012, Vol.287(39), pp.33001-13
    Description: Nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a master regulator of cellular antioxidant defense systems, and activation of this transcription factor is a promising strategy for protection of skin and other organs from environmental insults. To identify efficient Nrf2 activators in keratinocytes, we combined a chemical library screen with computer-based virtual screening. Among 14 novel Nrf2 activators, the most potent compound, a nitrophenyl derivative of 2-chloro-5-nitro-N-phenyl-benzamide, was characterized with regard to its molecular mechanism of action. This compound induced the expression of cytoprotective genes in keratinocytes isolated from wild-type but not from Nrf2-deficient mice. Most importantly, it showed low toxicity and protected primary human keratinocytes from UVB-induced cell death. Therefore, it represents a potential lead compound for the development of drugs for skin protection under stress conditions. Our study demonstrates that chemical library screening combined with advanced computational similarity searching is a powerful strategy for identification of bioactive compounds, and it points toward an innovative therapeutic approach against UVB-induced skin damage.
    Keywords: Benzamides -- Pharmacology ; Cytoprotection -- Drug Effects ; Keratinocytes -- Metabolism ; Nf-E2-Related Factor 2 -- Metabolism ; Ultraviolet Rays -- Adverse Effects
    E-ISSN: 1083-351X
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  • 10
    In: EMBO Molecular Medicine, April 2014, Vol.6(4), pp.442-457
    Description: The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline‐rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/“metabolizing acquired dioxin‐induced skin hamartomas” () patients. Indeed, ,2, and epigen were strongly expressed in cysts of patients and upregulated by dioxin in human keratinocytes in an 2‐dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of 2 in pathogenesis. Novel and unexpected activities of Nrf2 in the control of hair follicle and sebaceous gland homeostasis provide the first evidence for a role of 2 and downstream signaling in the pathogenesis of chloracne/ Transgenic mice expressing caNrf2 in keratinocytes have infundibular acanthosis, hyperkeratosis, and cysts formation upon aging. This phenotype developed due to Nrf2‐mediated upregulation of epigen, secretory leukocyte peptidase inhibitor, and small proline‐rich protein 2d. These target genes are upregulated in MADISH patients and after dioxin treatment of human keratinocytes by aryl hydrocarbon receptor (AHR) and NRF2 activation. Novel and unexpected activities of Nrf2 in the control of hair follicle and sebaceous gland homeostasis provide the first evidence for a role of 2 and downstream signaling in the pathogenesis of chloracne/
    Keywords: Acne ; Sebaceous Gland ; Nrf2 ; Oxidative Stress ; Skin
    ISSN: 1757-4676
    E-ISSN: 1757-4684
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