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Isosorbide di-(linoleate/oleate) stimulates pro-differentiation gene expression to restore the epidermal barrier and improve skin hydration

ABSTRACT: The breakdown of epidermal barrier and consequent loss of skin hydration is a feature of skin aging and eczematous dermatitis. Few treatments, however, resolve these underlying processes to provide full symptomatic relief. In this study, we generated a novel compound, isosorbide di-(linoleate/oleate) (IDL), by esterifying isosorbide with sunflower fatty acids. Topical effects of IDL in skin were compared to those of ethyl linoleate/oleate (EL), which has previously been shown to improve skin barrier function. Both IDL and EL down-regulated inflammatory gene expression, but IDL more effectively up-regulated the expression of genes associated with keratinocyte differentiation (e.g., KRT1, GRHL2, SPRR4). Consistent with this, IDL increased abundance of epidermal barrier proteins (filaggrin and involucrin) and prevented cytokine-mediated stratum corneum degradation. IDL also down-regulated expression of “unhealthy skin signature” genes linked to loss of epidermal homeostasis and uniquely repressed an interferon-inducible co-expression module activated in multiple skin diseases including psoriasis. In a double-blind placebo-controlled trial enrolling females with dry skin, 2% IDL lotion applied over 2 weeks significantly improved skin hydration and decreased transepidermal water loss (NCT04253704). These results demonstrate mechanisms by which IDL improves skin hydration and epidermal barrier function, supporting IDL as an effective intervention for treatment of xerotic pruritic skin.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157932 | GEO | 2020/11/16

REPOSITORIES: GEO

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Isosorbide fatty acid diesters have synergistic anti-inflammatory effects in cytokine-induced tissue culture models of atopic dermatitis

Project description:Atopic dermatitis (AD) is a chronic disease in which epidermal barrier disruption triggers Th2-mediated eruption of eczematous lesions. Topical emollients are a cornerstone of chronic management. This study evaluated efficacy of two plant-derived oil derivatives, isosorbide di-(linoleate/oleate) (IDL) and isosorbide dicaprylate (IDC), using AD-like tissue culture models. Treatment of reconstituted human epidermis with cytokine cocktail (IL-4 + IL-13 + TNF-α + IL-31) compromised the epidermal barrier, but this was prevented by co-treatment with IDL and IDC. Cytokine stimulation also dysregulated expression of keratinocyte (KC) differentiation genes whereas treatment with IDC or IDL+IDC up-regulated genes associated with early (but not late) KC differentiation. Although neither IDL nor IDC inhibited Th2 cytokine responses, both compounds repressed TNF-α-induced genes and IDL+IDC led to synergistic down-regulation of inflammatory (IL1B, ITGA5) and neurogenic pruritus (TRPA1) mediators. Treatment of cytokine-stimulated skin explants with IDC decreased lactate dehydrogenase (LDH) secretion by more than 50% (more than observed with cyclosporine) and in vitro LDH activity was inhibited by IDL and IDC. These results demonstrate anti-inflammatory mechanisms of isosorbide fatty acid diesters in AD-like skin models. Our findings highlight the multifunctional potential of plant oil derivatives as topical ingredients and support studies of IDL and IDC as therapeutic candidates.

2022-11-21 | GSE217468 | GEO

Isosorbide di-(linoleate/oleate) stimulates pro-differentiation gene expression to restore the epidermal barrier and improve skin hydration

Project description:Isosorbide di-(linoleate/oleate) stimulates pro-differentiation gene expression to restore the epidermal barrier and improve skin hydration

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SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation

Project description:SDR9C7 encodes an orphan short-chain dehydrogenase/reductase recently found mutated in ichthyosis. In a patient with SDR9C7 mutation and a mouse Sdr9c7 knockout model we show loss of covalent binding of epidermal ceramides to protein, a structural fault in the barrier. For reasons unresolved, protein binding requires lipoxygenase-catalyzed transformations of linoleic acid (18:2) esterified in ω-O-acylceramides. In Sdr9c7-/- epidermis, quantitative LC-MS assays revealed almost complete loss of a species of ω-O-acylceramide esterified with linoleate-9,10-trans-epoxy-11E-13-ketone; other acylceramides related to the lipoxygenase pathway were in higher abundance. Recombinant SDR9C7 catalyzed NAD-dependent dehydrogenation of linoleate 9,10-trans-epoxy-11E-13-alcohol to the corresponding 13-ketone, while ichthyosis mutants were inactive. We propose, therefore, that the critical requirement for lipoxygenases and SDR9C7 is in producing acylceramide containing the 9,10-epoxy-11E-13-ketone, a reactive moiety known for its non-enzymatic coupling to protein. This suggests a novel mechanism for coupling of ceramide to protein and provides important insights into skin barrier formation and pathogenesis.

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PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis

Project description:Mutations in PNPLA1 (patatin-like phospholipase domain containing 1) cause autosomal recessive congenital ichthyosis, but the mechanism involved remains unclear. Here we show that PNPLA1, an enzyme expressed in highly differentiated keratinocytes, plays a crucial role in the biosynthesis of acylceramide, a lipid component essential for skin barrier function. Pnpla1-deficient mice showed neonatal lethality due to epidermal permeability barrier defects with severe transepidermal water loss, decreased intercellular lipid lamellae in the stratum corneum, and impaired terminal differentiation of keratinocytes. In Pnpla1–/– epidermis, three unique linoleate-containing lipids, including acylceramides, acylglucosylceramides and (O-acyl)-ω-hydroxy fatty acids, were almost absent with reciprocal increases in their precursors ω-hydroxy (glucosyl)ceramides and ω-hydroxy fatty acids, indicating that PNPLA1 catalyzes the ω-O-esterification step with linoleic acid to form acylceramides. Our results suggest that PNPLA1 represents the missing piece in the process of acylceramide biosynthesis required for establishment of a permeability barrier.

2016-12-23 | GSE87682 | GEO

Alteration of keratinocyte gene expression as a result of Flg deficiency

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2021-01-01 | GSE158028 | GEO

Free fatty acids and TNF-alpha in hepg2/c3a cell culture

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2006-08-04 | GSE5441 | 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

Alteration of the whole skin gene expression as a result of Flg deficiency

Project description:Defects of filaggrin (FLG) compromise epidermal barrier function and represent an important known genetic risk factor for atopic dermatitis (AD), but also for systemic atopy, including allergic sensitization and asthma. A loss of epidermal barrier integrity can provide a significant stress for the cells in both the epidermis as well as the underlying dermal layer of the skin, either due to the increased moisture evaporation from the skin or increased penetration of the antigens and microflora into the lower layers. This analysis was therefore designed to understand the effect of this loss of barrier integrity on the total skin transcriptional profile.

2021-05-01 | GSE164623 | GEO

Expression data from mouse adult epidermis in response to physical or immune mediated damage

Project description:Whether epidermal factors play a primary role in immune-mediated skin diseases such as psoriasis is unknown. We now show that the pro-differentiation transcription factor Grainyhead-like 3 (GRHL3), essential during epidermal development but dispensable in adult skin homeostasis, is required for barrier repair after adult epidermal injury. Consistent with activation of a GRHL3-regulated repair pathway in psoriasis, we find GRHL3 up-regulation in lesional skin where GRHL3 binds known epidermal differentiation gene targets. Furthermore, we show the functionality of this pathway in the Imiquimod mouse model of immune-mediated epidermal hyperplasia where loss of Grhl3 exacerbates the epidermal damage response, conferring greater sensitivity to disease induction, delayed resolution of epidermal lesions, and resistance to anti-IL-22 therapy. ChIP-seq and gene expression profiling studies show that while GRHL3 regulates differentiation genes both in development and during repair from immune-mediated damage, it targets distinct sets of genes in the two processes. In particular, GRHL3 suppresses a number of alarmin and other pro-inflammatory genes after immune injury. This study identifies a GRHL3-regulated epidermal barrier repair pathway that suppresses disease initiation and helps resolve existing lesions in immune-mediated epidermal hyperplasia. A single timepoint was assessed after physical injury of the epidermal barrier and two timepoints were assessed after immune mediated injury of the epidermis following Imiquimod treatment (psoriasis mouse model)

2014-10-01 | E-GEOD-59384 | biostudies-arrayexpress

Conditional keratinocyte-specific ADAM17 knockout in mice alters skin homeostasis

2012-06-21 | GSE38830 | GEO

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