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Keratins control Nrf2 by regulating mitochondrial activity and barrier composition / Keratin-dependent TSLP expression suggests a link between skin blistering and atopic disease

ABSTRACT: The epidermal barrier protects the body against mechanical injury, infection and dehydration. The respective contribution of type I and type II keratins which form the major cytoskeleton in epidermal keratinocytes in barrier formation and stress protection is incompletely understood. Here, we reveal a novel mechanism by which keratins control anti-oxidant responses through barrier-dependent and cell-autonomous mechanisms. Mice lacking the entire type I (KtyI) or type II (KtyII) keratin gene clusters suffer from distinct prenatal barrier defects. Comparative transcriptome profiling identifies essential cornified envelope components and reveals strong upregulation of the bZIP transcription factor Nrf2 in situ. Isolated keratinocytes from both strains of mice show elevated mitochondrial oxygen consumption and Nrf2 activity, decreased upon keratin re-expression. We propose a model in which keratins control mitochondria-derived oxidative stress via Nrf2 activation. Our findings reveal major contributions of keratins to chronic inflammation and autoimmune disorders. Total RNA obtained from E18.5 embryo back skin from typeI and II keratin knockout compared with respective wild type.

ORGANISM(S): Mus musculus

SUBMITTER: Vinod Kumar

PROVIDER: E-GEOD-79590 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Keratins control Nrf2 by regulating mitochondrial activity and barrier composition / Keratin-dependent TSLP expression suggests a link between skin blistering and atopic disease

Project description:The epidermal barrier protects the body against mechanical injury, infection and dehydration. The respective contribution of type I and type II keratins which form the major cytoskeleton in epidermal keratinocytes in barrier formation and stress protection is incompletely understood. Here, we reveal a novel mechanism by which keratins control anti-oxidant responses through barrier-dependent and cell-autonomous mechanisms. Mice lacking the entire type I (KtyI) or type II (KtyII) keratin gene clusters suffer from distinct prenatal barrier defects. Comparative transcriptome profiling identifies essential cornified envelope components and reveals strong upregulation of the bZIP transcription factor Nrf2 in situ. Isolated keratinocytes from both strains of mice show elevated mitochondrial oxygen consumption and Nrf2 activity, decreased upon keratin re-expression. We propose a model in which keratins control mitochondria-derived oxidative stress via Nrf2 activation. Our findings reveal major contributions of keratins to chronic inflammation and autoimmune disorders.

2016-03-26 | GSE79590 | GEO

Keratin-dependent TSLP expression suggests a link between skin blistering and atopic disease

Project description:Atopic dermatitis (AD) is a pruritic and inflammatory disorder characterized by elevated levels of thymic stromal lymphopoietin (TSLP). Pruritus is prevalent in epidermolysis bullosa (EB). Currently, epidermal barrier disruption is known to trigger TSLP upregulation, however, mechanisms controlling TSLP expression remain incompletely understood. Tslp levels were highly upregulated in the epidermis and in the serum of keratin-deficient mice. Cultured keratinocytes either lacking keratins or expressing the dominant K14p.Arg131Pro show highly increased TSLP. Re-expression of wild-type K14 normalized TSLP levels. We demonstrate that keratins regulate Tslp expression in parts through MEK1/2 activation. The finding that 8 out of 17 EBS patients show elevated TSLP serum levels supports a major role of keratins in TSLP regulation. Our data identify a novel, keratin-dependent and cell-intrinsic regulation of Tslp. Elevated TSLP levels likely explain the high prevalence of pruritus in EBS and additional forms of EB, suggesting TSLP as novel biomarker for pruritus in EB. MEK1/2, in addition to calcineurin inhibitors, might be suitable drugs to treat itch in EB. Investigation was carried out using Keratin deficient keratinocytes isolated from typeI keratin mice.

2016-03-26 | E-GEOD-79596 | biostudies-arrayexpress

Keratin-dependent TSLP expression suggests a link between skin blistering and atopic disease

2016-03-26 | GSE79596 | GEO

Genome-wide analysis of gene expression in Krt1+/+ versus Krt1-/- epidermis and full-thickness skin.

Project description:Keratin 1 (KRT1) and its heterodimer partner keratin 10 (KRT10) constitute the intermediate filament cytoskeleton of suprabasal skin keratinocytes. They participate in formation of the epidermal barrier, which protects against dehydration and inflammation. Mutations in KRT1 cause keratinopathic ichthyosis with erythema, recurrent inflammation, and barrier defects. Here, we show that genetic deletion of Krt1 in mice causes a defective inside-out epidermal barrier, pre- and postnatal increases in Mrp8/Mrp14, interleukin (IL) 18, IL-33, and thymic stromal lymphopoietin (TSLP) in skin extracts, and systemic release of IL-18 into newborn serum. Perinatal lethality was partially rescued by treatment with glucocorticoids to promote barrier repair or with IL- 18-blocking antibodies in utero. In human keratinocytes, IL-18 release was cellautonomous and caspase-1-dependent, indicating KRT1-dependent inflammasome activation. Our data reveal a novl function of KRT1 in controlling inflammasome activity and stimulating barrier formation, thereby integrating the keratin cytoskeleton into the epidermal immune response. In view of their widespread expression, keratins merit investigation of their functions in inflammatory conditions, including asthma and inflammatory bowel disorders. Total RNA was obtained from epidermis or full-thickness skin of Krt1+/+ and Krt1-/- mice (C57BL/6 background) at P0 (newborn).

2012-12-01 | E-GEOD-32951 | biostudies-arrayexpress

Genome-wide analysis of gene expression in Krt1+/+ versus Krt1-/- epidermis and full-thickness skin.

2012-12-01 | GSE32951 | GEO

Single cell transcriptomics defines keratinocyte differentiation in avian scutate scales

Project description:Epidermal keratinocytes form cornified skin appendages such as scutate scales on the legs of birds. Here, we investigated the molecular pathways of keratinocyte differentiation in chicken scutate scales by single cell transcriptomics. We identified two distinct populations of differentiated keratinocytes. The first type of differentiated keratinocytes is characterized by mRNAs encoding scale-type corneous beta-proteins (CBPs), also known as beta-keratins and cysteine-rich keratins, indicating that these cells form hard scales. The second type of differentiated keratinocytes contains mRNAs encoding keratinocyte-type CBPs and cysteine-poor keratins, indicating that these cells form the soft interscale epidermis. Immunostaining with a newly raised antibody confirmed that keratin 9-like cysteine-rich 2 (KRT9LC2) or Hard Acid Sauropsid-specific 2 (HAS2) keratin, which is a marker of the first type of keratinocytes, is expressed in the suprabasal epidermal layers of scutate scales but not in interscale epidermis. Furthermore, mRNA of CTNN1B, previously implicated in scale placode formation, was enriched in differentiated scale keratinocytes, whereas genes involved in lipid metabolism, such as ELOVL4 and FADS1 were enriched in keratinocytes of the interscale epidermis. In conclusion, this study defines the gene expression programs that build the scutate scales and interscale epidermis of birds.

2021-07-09 | GSE179690 | GEO

Conditional keratinocyte-specific ADAM17 knockout in mice alters skin homeostasis

Project description:This study investigates the role of ADAM17 (a disintegrin and metalloproteinase 17) in skin homeostasis. Here, we show that mice lacking ADAM17 in keratinocytes have a normal epidermal barrier and skin architecture at birth, but develop pronounced defects in epidermal barrier integrity soon after birth and chronic dermatitis as adults. The dysregulated expression of epidermal differentiation proteins becomes evident 2 days after birth, followed by transepidermal water loss and inflammatory immune cell infiltration. Our results identify a previously unappreciated critical role of the ADAM17/EGFR signaling axis in maintaining the homeostasis of the postnatal epidermal barrier. The genome-wide effects of ADAM17 deficiency were analyzed using Agilent Whole Mouse Genome microarrays. Conditional keratinocyte-specific ADAM17 knockout mice were generated by crossing Adam17flox/flox mice with keratin-14-Cre (Krt14-Cre) transgenic mice. Adam17flox/+Krt14-Cre mice were mated with Adam17flox/flox mice to generate pups of Adam17flox/flox Krt14-Cre positive (cKO) and Krt14-Cre negative (wild-type) control littermates. The genetic background was a mix of 129Sv and C57BL/6. As material, back skin tissue biopsies (postnatal day 10) from n = 2 wild-type skin and n = 2 ADAM17 epidermal KO skin (matched WT-cKO pairs from two different litters) were used in this study.

2012-06-20 | E-GEOD-38830 | biostudies-arrayexpress

Gene expression profile of primary epidermal keratinocytes (HEKs) stimulated with lawsone

Project description:The study aimed to interrogate whether the 1,4-naphtoquinone derivative lawsone activates the aryl hydrocarbon receptor (AhR) downstream transcriptional program in keratinocytes and is capable of modulating skin homeostasis. The study has been performed on human primary epidermal keratinocytes (HEKs), which represent the first line of defense against exogenous molecules. HEK cells were treated with the vehicle control DMSO (control), stimulated with lawsone or with the TLR2 ligand Pam2CSK4. Transcriptional profiles of HEK cells were studied to investigate the regulation of AhR -related genes, Nrf2-related genes and epidermal differentiation and keratin genes. We demonstrated that lawsone was sensed by keratinocytes and activated AhR. In particular, lawsone efficiently activated the transcriptional program of AhR and promoted keratinocyte differentiation.

2019-08-06 | GSE99901 | GEO

Keratinocyte-Macrophage Crosstalk by the Nrf2/Ccl2/EGF Signaling Axis Orchestrates Tissue Regeneration

Project description:Unveiling the molecular mechanisms underlying tissue regeneration provides new opportunities to develop treatments for diabetic ulcers and other chronic skin lesions. Here, to gain insight into critical wound response mechanisms regulated by epidermal Nrf2, we micro dissected a ~2.5mm concentric ring around the 10mm wound at 5 days-post-wounding (DPW) and used flow cytometry to isolate wound-associated keratinocytes from Nrf2 +/+ Ker and Nrf2 ∆/∆ Ker mice for bulk RNA-seq. Combining in vivo and ex vivo data with next generation sequencing, we show that Ccl2 secretion by epidermal keratinocytes is directly orchestrated by Nrf2, a prominent transcriptional regulator of tissue regeneration that is activated early after cutaneous injury. Through a unique feedback mechanism, we find that Ccl2 from epidermal keratinocytes not only drives chemotaxis of macrophages into the wound, but also triggers macrophage expression of EGF, which in turn activates basal epidermal keratinocyte proliferation. Notably, we find dysfunctional activation of Nrf2 in epidermal keratinocytes of diabetic mice after wounding, which in part, explains regenerative impairments associated with diabetes. These findings provide mechanistic insight into the critical relationship between keratinocyte-macrophage signaling during tissue regeneration, providing the basis for continued investigation of the therapeutic value of Nrf2.

2020-10-12 | GSE159361 | GEO

Knockouts of both Vitamin D receptor (VDR) and its coactivator Med1 enhance epidermal permeability barrier function

Project description:Vitamin D receptor (VDR) is crucial for formation of epidermal permeability barrier and ceramide production, while mediator complex subunit 1 (Med1), a coactivator of VDR, mediates the action of VDR. VDR deficiency compromises epidermal permeability barrier in mice. Hence, we are investigating the dual role of VDR and Med1 in epidermal permeability barrier. Mice with VDR and Med1 specifically deleted in Keratin 14 expressing keratinocytes (DKO) by Cre-lox strategy are utilized. The mice with both floxed VDR and Med1 but no Cre serve as control. The data showed here that knockouts of both VDR and Med1 enhanced epidermal permeability barrier in mice, accompanied by increased expression levels of mRNA for keratinocyte differentiation marker-related proteins, fatty acid and ceramide productions, which all are required for formation of epidermal permeability barrier. Moreover, expression levels of mRNA for ceramide transporter (ABCA12) were also elevated in DKO mice vs. knockout of either VDR or Med1 alone. Collectively, these results demonstrate that knockouts of both VDR and Med1 enhance epidermal permeability barrier function via upregulating expression levels of mRNA for epidermal differentiation marker-related proteins and lipid synthetic enzymes, suggesting additional signaling pathway(s) involve regulatory role of VDR/Med1 in epidermal function.

2020-09-14 | GSE157887 | GEO

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