Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch

Hasan, Zobaer; Kitamura, Miho; Kawai, Mami; Ohira, Moto; Mori, Kazuya; Shoju, Shintaro; Takagi, Kohei; Tsukamoto, Kosei; Kawai, Yu; Inoue, Akihiro

doi:10.1016/j.tiv.2019.03.005

Cited by 14 publications

(15 citation statements)

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“…Clemmensen et al (2010) observed epidermal expression of MMP-3 in experimental irritant contact dermatitis in human skin and suggested that secretion of this protease may release GFs that are sequestered in the extracellular matrix as part of a tissue repair process. The gene transcript for MMP-3 has been detected previously by us and others on analysis of either reconstituted human epidermis or fullthickness HSE when these models were treated with several irritants (Cottrez et al, 2016(Cottrez et al, , 2015Hasan et al, 2019;Petry et al, 2018), underscoring its significance as a marker of skin irritation.…”

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confidence: 70%

“…Gene expression analysis for a panel of 22 genes previously associated with a LA response ( Hasan et al., 2019 ) was performed by qPCR and fold-changes in expression compared with vehicle-treated CONs ( Figure 3 ). Treatment of skin with LA revealed a significant fold-increase in AFT3 ( P = 0.0027), DDIT ( P < 0.0001), F2RL2 ( P = 0.0192), fibronectin gene FN-1 ( P < 0.0001), signal transducer and activator of transcription gene STAT-1 ( P = 0.0204), HMGB2 ( P < 0.0001), IL1β ( P < 0.0001), IL-6 ( P = 0.0009), MAP3K8 ( P = 0.0133), and transit amplifying cell gene TAC-1 ( P < 0.0001), and a fold-decrease in expression observed for matrix metalloproteinase (MMP) gene MMP-3 ( P = 0.0364) compared with CON ( Figure 3 a).…”

Section: Resultsmentioning

confidence: 99%

“…Characterization of skin sensitivity and irritancy at the gene level is rapidly gaining pace and has driven the development of several gene expression-based assay systems using either reconstituted human epidermis skin equivalents that consist solely of a stratified squamous epidermis ( Hasan et al., 2019 ; Saito et al., 2017 ) or full-thickness HSE (consisting of both epidermis and a fibroblast-populated dermis), with SENS-IS being the most advanced in terms of validation against a large panel of chemicals ( Cottrez et al., 2016 ). We recently reported whole genome expression profiles of reconstituted human epidermis in response to LA, identifying several genes highly associated with irritancy and sensitization ( Hasan et al., 2019 ). Here, we report the use of a full-thickness HSE system based on immortalized skin KCs and show that a 22-gene panel can discriminate between chemicals known to act as irritants from those that do not.…”

Section: Introductionmentioning

confidence: 99%

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Determination of Chemical Irritation Potential Using a Defined Gene Signature Set on Tissue-Engineered Human Skin Equivalents

et al. 2021

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There are no physical or visual manifestations that define skin sensitivity or irritation; a subjective diagnosis is made on the basis of the evaluation of clinical presentations, including burning, prickling, erythema, and itching. Adverse skin reaction in response to topically applied products is common and can limit the use of dermatological or cosmetic products. The purpose of this study was to evaluate the use of human skin equivalents based on immortalized skin keratinocytes and evaluate the potential of a 22-gene panel in combination with multivariate analysis to discriminate between chemicals known to act as irritants and those that do not. Test compounds were applied topically to full-thickness human skin equivalent or human ex vivo skin and gene signatures determined for known irritants and nonirritants. Principle component analysis showed the discriminatory potential of the 22-gene panel. Linear discrimination analysis, performed to further refine the gene set for a more high-throughput analysis, identified a putative seven-gene panel (IL-6, PTGS2, ATF3, TRPV3, MAP3K8, HMGB2, and matrix metalloproteinase gene MMP-3) that could distinguish potential irritants from nonirritants. These data offer promise as an in vitro prediction tool, although analysis of a large chemical test set is required to further evaluate the system.

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confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Determination of Chemical Irritation Potential Using a Defined Gene Signature Set on Tissue-Engineered Human Skin Equivalents

et al. 2021

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“…IL33 has been shown to accumulate in inflamed skin in a mouse model of poison ivyinduced allergic dermatitis and contribute to itching (20). IL-1a is present in epidermal keratinocytes and is upregulated in response to chemical exposure associated with stinging and itch (21). IL33 and IL-1a may, therefore, contribute to mediating the itch that is often perceived during the formation of suction blisters.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Markers in Suction Blister Fluid: A Comparative Study Between Interstitial Fluid and Plasma

et al. 2020

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Background: Biomarker analysis allows for the detection and prediction of disease as well as health monitoring. The use of interstitial fluid (ISF) as a matrix for biomarkers has recently gained interest. This study aimed to compare levels of inflammatory markers in ISF from suction blister fluid (SBF) and plasma. Methods: Plasma and SBF were collected from 18 healthy individuals. Samples were analyzed for 92 inflammation-related protein biomarkers by Proximity Extension Assay (PEA). Protein profiles in the two matrices were compared using traditional and multivariate statistics. Results: Out of 92 targeted proteins, 70 were successfully quantified in both plasma and SBF. Overall, plasma and SBF displayed distinct protein profiles with up to 40-fold difference in abundance of specific proteins. The levels of 25 proteins were significantly correlated between plasma and SBF and several of these were recognized as potential markers to monitor health using ISF. Conclusions: Skin ISF and plasma have unique protein profiles but many inflammatory markers are proportionally related between the matrices at the individual level. ISF is a promising biofluid for the monitoring of biomarkers in clinical studies and routine analyses.

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“…FLG2 is also expressed in the keratohyalin granules in the granular layer [5,59]. The expression of FLG and FLG2 is downregulated in skin treated with 5% or 10% lactic acid, with such downregulation often used to define sensitive skin [60]. The expression of FLG and FLG2 has also been reported to be downregulated by tape stripping [61].…”

Section: Roles Of Ivl Lor Flg and Flg2 In Epidermal Barrier Formationmentioning

confidence: 99%

Regulation of Filaggrin, Loricrin, and Involucrin by IL-4, IL-13, IL-17A, IL-22, AHR, and NRF2: Pathogenic Implications in Atopic Dermatitis

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2020

IJMS

226

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Atopic dermatitis (AD) is an eczematous, pruritic skin disorder with extensive barrier dysfunction and elevated interleukin (IL)-4 and IL-13 signatures. The barrier dysfunction correlates with the downregulation of barrier-related molecules such as filaggrin (FLG), loricrin (LOR), and involucrin (IVL). IL-4 and IL-13 potently inhibit the expression of these molecules by activating signal transducer and activator of transcription (STAT)6 and STAT3. In addition to IL-4 and IL-13, IL-22 and IL-17A are probably involved in the barrier dysfunction by inhibiting the expression of these barrier-related molecules. In contrast, natural or medicinal ligands for aryl hydrocarbon receptor (AHR) are potent upregulators of FLG, LOR, and IVL expression. As IL-4, IL-13, IL-22, and IL-17A are all capable of inducing oxidative stress, antioxidative AHR agonists such as coal tar, glyteer, and tapinarof exert particular therapeutic efficacy for AD. These antioxidative AHR ligands are known to activate an antioxidative transcription factor, nuclear factor E2-related factor 2 (NRF2). This article focuses on the mechanisms by which FLG, LOR, and IVL expression is regulated by IL-4, IL-13, IL-22, and IL-17A. The author also summarizes how AHR and NRF2 dual activators exert their beneficial effects in the treatment of AD.

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Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch

Cited by 14 publications

References 40 publications

Determination of Chemical Irritation Potential Using a Defined Gene Signature Set on Tissue-Engineered Human Skin Equivalents

Determination of Chemical Irritation Potential Using a Defined Gene Signature Set on Tissue-Engineered Human Skin Equivalents

Inflammatory Markers in Suction Blister Fluid: A Comparative Study Between Interstitial Fluid and Plasma

Regulation of Filaggrin, Loricrin, and Involucrin by IL-4, IL-13, IL-17A, IL-22, AHR, and NRF2: Pathogenic Implications in Atopic Dermatitis

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