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de Ávila RI, Ljungberg Silic L, Carreira‐Santos S, Merényi G, Bergendorff O, Zeller KS. In vitro characterisation of a novel rubber contact allergen in protective gloves. Contact Dermatitis 2025; 92:61-71. [PMID: 39183491 PMCID: PMC11669566 DOI: 10.1111/cod.14682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/30/2024] [Accepted: 08/12/2024] [Indexed: 08/27/2024]
Abstract
BACKGROUND Allergic contact dermatitis (ACD) from protective gloves is often caused by rubber additives, such as accelerators. However, while accelerator-free rubber gloves are available, they still cause ACD in some individuals. OBJECTIVES A new allergen, 2-cyаnоethyl dimethyldithiocarbamate, (CEDMC), has recently been identified in accelerator-free gloves, and we here provide a first in vitro characterisation of CEDMC in a dendritic cell (DC)-like cell model along with three reference sensitizer rubber chemicals, consisting of tetraethylthiuram disulfide (TETD) and two xanthogenates. METHODS Cellular responses after the exposure to the rubber chemicals were assessed using a transcriptomic approach, multiplex cytokine secretion profiling, and flow cytometry to determine DC model activation marker expression and apoptosis induction. RESULTS CEDMC and all other sensitizers were classified as strong skin sensitizers with the transcriptomic approach. They all significantly increased IL-8 secretion and exposure to all except one increased CD86 DC activation marker expression. When tested, CEDMC induced apoptosis, however, delayed compared to TETD. CONCLUSIONS The in vitro data corroborate CEDMC, TETD, and investigated xanthogenates as skin sensitizers. Transcriptomic analyses further reveal unique cellular responses induced by CEDMC, which together with future study can contribute to better understanding of cellular mechanisms underlying the sensitising capacity of rubber chemicals.
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Affiliation(s)
- Renato Ivan de Ávila
- Department of ImmunotechnologyLund UniversityLundSweden
- Present address:
Unilever Safety and Environmental Assurance Centre (SEAC), Colworth Science ParkBedfordshireUK
| | - Linda Ljungberg Silic
- Department of Occupational and Environmental Dermatology (DOED)Lund University, Skåne University HospitalMalmöSweden
| | | | - Gábor Merényi
- Department of ImmunotechnologyLund UniversityLundSweden
| | - Ola Bergendorff
- Department of Occupational and Environmental Dermatology (DOED)Lund University, Skåne University HospitalMalmöSweden
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2
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Peyneau M, Zeller M, Paulet V, Noël B, Damiens MH, Szely N, Natsch A, Pallardy M, Chollet-Martin S, de Chaisemartin L, Kerdine-Römer S. Quaternary ammoniums activate human dendritic cells and induce a specific T-cell response in vitro. Allergol Int 2025; 74:105-114. [PMID: 39237430 DOI: 10.1016/j.alit.2024.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 06/25/2024] [Accepted: 07/11/2024] [Indexed: 09/07/2024] Open
Abstract
BACKGROUND In many countries, neuro-muscular blocking agents (NMBAs) are the first cause of perioperative anaphylaxis. Epidemiological studies identified pholcodine, a quaternary ammonium-containing opiate as one of the sensitization sources. However, NMBA anaphylaxis exists in countries where pholcodine was unavailable, prompting the hypothesis of other sensitizing molecules, most likely quaternary ammonium compounds (QACs). Indeed, QACs are commonly used as disinfectants, antiseptics, preservatives, and detergents. Occupational exposure to QACs has been reported as a risk factor for NMBA anaphylaxis, but little is known about the sensitization mechanism and the capacity of these molecules to elicit an immune response. We aimed to establish the immunogenicity of QACs representative of the main existing chemical structures. METHODS We measured the sensitization potential of seven QACs (two polyquaterniums, three alkyl-ammoniums and two aromatic ammoniums) by using two standard dendritic cells (DCs) models (THP-1 cell line and monocyte derived-dendritic cells). The allergenicity of the sensitizing compounds was further tested in heterologous and autologous T-cell-DC co-culture models. RESULTS Amongst the seven molecules tested, four could modulate activation markers on DCs, and thus can be classified as chemical sensitizers (polyquaterniums-7 and -10, ethylhexadecyldimethylammonium and benzethonium). This activation was accompanied by the secretion of pro-inflammatory and maturation cytokines. Furthermore, activation by polyquaternium-7 could induce T-cell proliferation in heterologous and autologous coculture models, demonstrating that this molecule can induce a specific CD4+ T cell response. CONCLUSIONS We provide evidence at the cellular level that some QACs can elicit an immune response, which could be in line with the hypothesis of these molecules' role in NMBA sensitization.
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Affiliation(s)
- Marine Peyneau
- Université Paris-Saclay, Inserm, Inflammation, Microbiome & Immunosurveillance, Orsay, France; AP-HP, Service d'Immunologie Biologique, DMU BIOGEM, Hôpital Bichat, Paris, France
| | - Mathilde Zeller
- Université Paris-Saclay, Inserm, Inflammation, Microbiome & Immunosurveillance, Orsay, France
| | - Virginie Paulet
- Université Paris-Saclay, Inserm, Inflammation, Microbiome & Immunosurveillance, Orsay, France
| | - Benoît Noël
- Université Paris-Saclay, Inserm, Inflammation, Microbiome & Immunosurveillance, Orsay, France
| | - Marie-Hélène Damiens
- Université Paris-Saclay, Inserm, Inflammation, Microbiome & Immunosurveillance, Orsay, France
| | - Natacha Szely
- Université Paris-Saclay, Inserm, Inflammation, Microbiome & Immunosurveillance, Orsay, France
| | | | - Marc Pallardy
- Université Paris-Saclay, Inserm, Inflammation, Microbiome & Immunosurveillance, Orsay, France
| | - Sylvie Chollet-Martin
- Université Paris-Saclay, Inserm, Inflammation, Microbiome & Immunosurveillance, Orsay, France; AP-HP, Service d'Immunologie Biologique, DMU BIOGEM, Hôpital Bichat, Paris, France
| | - Luc de Chaisemartin
- Université Paris-Saclay, Inserm, Inflammation, Microbiome & Immunosurveillance, Orsay, France; AP-HP, Service d'Immunologie Biologique, DMU BIOGEM, Hôpital Bichat, Paris, France
| | - Saadia Kerdine-Römer
- Université Paris-Saclay, Inserm, Inflammation, Microbiome & Immunosurveillance, Orsay, France.
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Zhao J, Yan S, Ma X, Song Y, Pan Y. Nrf2 regulates the activation of THP-1 cells induced by chloral hydrate. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 256:114841. [PMID: 36989555 DOI: 10.1016/j.ecoenv.2023.114841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 03/21/2023] [Accepted: 03/25/2023] [Indexed: 06/19/2023]
Abstract
Trichloroethylene (TCE) triggers a severe hypersensitivity syndrome in the occupational population dependent on dendritic cells (DCs). Chloral hydrate (CH), the major oxidative metabolite of TCE, has been proved to be the culprit causative substance of TCE-induced hypersensitivity by human patch tests. Because redox imbalance is essential for chemical sensitizers-induced maturation of DCs, we predicted that CH would activate DCs by the nuclear factor E2-related factor 2 (Nrf2)-mediated antioxidant response. This study selected THP-1 cells as the in vitro DC model, and we evaluated the cell activation markers, intracellular oxidative stress, and Nrf2 pathway related genes expression in response to CH in THP-1 cells. CH displayed significant stimulation of THP-1 cells activation, including CD54 and CD86 expression, IL-8 release, and cell migration, and damaged the redox balance by triggering ROS generation, GSH consumption, and antioxidase activities modulation. The levels of Nrf2 and its downstream genes (HO-1 and NQO1) in mRNA and protein expressions were upregulated by CH, and CH also promoted the nuclear translocation of Nrf2. Subsequently, we investigated the effects of antioxidant on Nrf2-mediated cell defense in CH treated cells. Pretreatment with curcumin dramatically reduced cell activation and oxidative stress triggered by CH in THP-1 cells. We also confirmed the specific role of Nrf2 in CH-induced cell activation using NRF2-knockout cells. Deficiency of Nrf2 inhibited cell activation and downregulated HO-1 and NQO1 expression in CH-challenged cells. These findings suggest that Nrf2-dependent redox homeostasis plays a pivotal role in CH-induced activation of THP-1 cells, thereby providing new knowledge of the allergen as well as the molecular mechanism involving in TCE-induce hypersensitivity syndrome.
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Affiliation(s)
- Jinfeng Zhao
- Department of Cosmetics, College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing 100048, China; Beijing Key Laboratory of Plant Research and Development, Beijing 100048, China
| | - Shiyu Yan
- Department of Cosmetics, College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing 100048, China; Beijing Key Laboratory of Plant Research and Development, Beijing 100048, China
| | - Xue Ma
- Department of Cosmetics, College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing 100048, China; Beijing Key Laboratory of Plant Research and Development, Beijing 100048, China
| | - Yanqing Song
- Department of Cosmetics, College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing 100048, China; Beijing Key Laboratory of Plant Research and Development, Beijing 100048, China
| | - Yao Pan
- Department of Cosmetics, College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing 100048, China; Beijing Key Laboratory of Plant Research and Development, Beijing 100048, China.
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Hardonnière K, Salman S, Ali ZE, Vallion R, De Bourayne M, Pallardy M, Kerdine-Römer S. P10-10 Accumulation of Nrf2 controlled by CK2 in dendritic cells plays a role in the chemical sensitizer-induced inflammation response. Toxicol Lett 2022. [DOI: 10.1016/j.toxlet.2022.07.441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Balaha MF, Ahmed NJ, Almalki ZS, Alahmari AK, Alshehri AM, Soliman GA, Hamad AM. Epimedin A ameliorates DNFB-induced allergic contact dermatitis in mice: Role of NF-κB/NLRP3-driven pyroptosis, Nrf2/HO-1 pathway, and inflammation modulation. Life Sci 2022; 302:120653. [PMID: 35598657 DOI: 10.1016/j.lfs.2022.120653] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/15/2022] [Accepted: 05/16/2022] [Indexed: 11/29/2022]
Abstract
AIMS The present study aimed to investigate the potential of epimedin A to ameliorate DNFB-induced allergic contact dermatitis (CD) and reveal its potential underlying mechanisms of action, emphasizing its role in modulating NF-κB/NLRP3, Nrf2/HO-1 pathways, and inflammation. MAIN METHODS Seven-week-old BALB/c mice received epimedin A orally for 11 days at doses of 5, 10, or 20 mg/kg/day, starting from the seventh day of DNFB-inducing CD. KEY FINDINGS Epimedin A dose-dependently ameliorated DNFB-induced CD, as revealed by the repression of the mice's scratching behavior, dermatitis score, ear thickness and weight, and ear tissue's histopathological changes, and area percent of collagen fibers induced by DNFB. These potentials were due to the NF-κB/NLRP3 pathway suppression and the Nrf2 pathway enhancement, as demonstrated by the reduction of NF-κB, NLRP3, ASC, caspase-1, and 8 mRNA expression, and NF-κBp65, IL-1β, MDA levels, and NF-κBp65 binding activity, along with the enhancement of the Nrf2, HO-1, IκB-α, GSH levels, SOD activity, and Nrf2 binding activity. Besides, it suppressed ear tissues' NLRP3 and caspase-8 induced pyroptosis by suppressing the ear tissues' caspase-1, 8, GSDMD upregulation, and LDH activity. Additionally, it repressed the local inflammatory reaction of ear tissue, as evidenced by the reduction of the elevated inflammatory cytokines (IL-1β, IL-6, Il-4, TNF-α, and IFN-γ), the serum level of t-IgE, DNFB s-IgE, s-IgE/t-IgE ratio, and the abrogation of the ear tissues histopathological changes. SIGNIFICANCE Epimedin A is a novel, hopeful, natural therapeutic agent for CD by modulating NF-κB/NLRP3, Nrf2 pathways, and inflammation.
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Affiliation(s)
- Mohamed F Balaha
- Clinical Pharmacy Department, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; Pharmacology Department, Faculty of Medicine, Tanta University, El-Gish Street, Tanta 31527, Egypt.
| | - Nehad J Ahmed
- Clinical Pharmacy Department, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Ziyad S Almalki
- Clinical Pharmacy Department, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Abdullah K Alahmari
- Clinical Pharmacy Department, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Ahmed M Alshehri
- Clinical Pharmacy Department, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Gamal A Soliman
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Abubaker M Hamad
- Basic Sciences Department, Preparatory Year Deanship, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; Department of Histopathology and Cytopathology, Faculty of Medical Laboratory Sciences, University of Gezira, Wad Madani, Sudan
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Vallion R, Kerdine-Römer S. Regulation of the immune response to contact sensitizers by Nrf2. Contact Dermatitis 2022; 87:13-19. [PMID: 35165896 DOI: 10.1111/cod.14073] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 01/17/2022] [Accepted: 02/04/2022] [Indexed: 11/28/2022]
Abstract
The skin is frequently exposed to chemical stress by organic chemicals or metal ions that can directly or indirectly challenge its immune components and may lead to T cell-mediated delayed type hypersensitivity reactions. The disruption of the skin's homeostasis by exposure to contact sensitizers can trigger an inflammatory immune response that results in eczema and allergic contact dermatitis. The recognition of these chemicals depends on Pattern Recognition Receptors expression on sentinel skin cells, mainly the innate resident immune cells orchestrating the skin's immune response and involving both oxidative and inflammatory pathways. The main driver of these both pathways is the Nrf2/Keap1 pathway, a major ubiquitous regulator of cellular oxidative and electrophilic stress, activated in various innate immune cells of the skin, including keratinocytes and epidermal Langerhans cells in the epidermis and dermal dendritic cells in the dermis. Nrf2 also shows a strong protective capacity by down-regulating inflammatory pathways. In this review, the important role of Nrf2 in the regulation of the immune response to contact sensitizers will be discussed and highlighted. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Romain Vallion
- Université Paris-Saclay, Inserm, Inflammation microbiome immunosurveillance, Châtenay-Malabry, France.,Safety Assessment Department, Pierre Fabre Dermo Cosmétique, Toulouse, France
| | - Saadia Kerdine-Römer
- Université Paris-Saclay, Inserm, Inflammation microbiome immunosurveillance, Châtenay-Malabry, France
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7
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Audry A, Mathiot J, Muller S, Coiscaud A, Langonné I, Battais F, Leininger B, Sponne I. A new cytometry-based method reveals an accumulation of Nrf2 in dendritic cells exposed to two respiratory sensitizers. Toxicol Res (Camb) 2021; 10:1223-1227. [PMID: 34956624 PMCID: PMC8692752 DOI: 10.1093/toxres/tfab101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 10/04/2021] [Accepted: 10/12/2021] [Indexed: 10/20/2023] Open
Abstract
The mechanisms underlying chemical respiratory sensitization are incompletely understood. One of the major cell types involved in this pathology are dendritic cells. In this study, the mechanisms of the NRF2-Keap1 pathway were studied using a bone marrow-derived dendritic cell model exposed to two respiratory sensitizers: ammonium hexachloroplatinate (HCP) and ammonium tetrachloroplatinate (ATCP). Expression levels for two Nrf2-regulated genes, hmox1 and srxn1, were analyzed by real time-quantitative polymerase chain reaction. A flow cytometry-based method was also developed to measure intracellular Nrf2 accumulation in dendritic cells following exposure. Exposure to HCP and ATCP increased both hmox1 and srxn1 gene expression, and was associated with accumulation of Nrf2 protein in cells. Overall, these results show that the respiratory sensitizers, in addition to skin sensitizers, can also induced markers associated with NRF2-Keap1 pathway activation in dendritic cells. This study contributes to a better understanding of the adverse outcome of respiratory sensitization.
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Affiliation(s)
- Adrien Audry
- Correspondence address. Department of Toxicology and Biometrology, National Institute for Research and Safety (INRS), rue du Morvan – 54500 Vandœuvre-ès-Nancy, France. Tel: +33 3 83 50 20 00; E-mail:
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8
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Lichter J, Silva E Sousa M, Peter N, Sahli F, Vileno B, Kuresepi S, Gourlaouen C, Giménez-Arnau E, Blömeke B. Skin sensitization to fragrance hydroperoxides: interplay between dendritic cells, keratinocytes and free radicals. Br J Dermatol 2020; 184:1143-1152. [PMID: 33205411 DOI: 10.1111/bjd.19685] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Skin sensitization to hydroperoxides (R-OOHs) of the commonly used fragrance terpenes limonene, linalool and citronellol is frequently reported. R-OOHs are believed to initiate the process leading to sensitization and allergic contact dermatitis through mechanisms involving radical intermediates. Thus, radical intermediates, keratinocytes and dendritic cells (DCs) may act in concert to initiate the process. OBJECTIVES To evaluate individual DC activation profiles by R-OOHs in the context of keratinocytes with regard to frequency, specificity and magnitude of upregulation. METHODS We used 2D and 3D cocultures with keratinocytes/reconstructed human epidermis (RHE) and DCs to evaluate cell surface levels of the costimulatory molecules CD86, CD80 and the adhesion molecule CD54 on cocultured DCs. Analysis of radical formation from limonene hydroperoxides in RHE was performed using electron paramagnetic resonance combined with the spin trapping technique. RESULTS R-OOHs induce donor-dependent DC activation. Major differences were found between the limonene-OOHs. Limonene-1-OOH was stronger with respect to both frequency and magnitude of response. Using a 3D coculture model, no DC activation was detected after topical application of 0·2% limonene-OOHs (20 µg cm-2 ), while 1·2% limonene-1-OOH or 2% limonene-2-OOH induced DC activation. Furthermore, we demonstrated differences in the carbon and oxygen radicals formed from the limonene-OOHs using RHE, mimicking what may happen in vivo. CONCLUSIONS We report clear individual differences in DC maturation induced by the most important hydroperoxides. Response rates and magnitude of response both indicate that very small structural alterations in the hydroperoxides are translated into specific DC responses. In addition, we provide more insight into the amounts of hydroperoxides that can activate DCs and induce sensitization.
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Affiliation(s)
- J Lichter
- Department of Environmental Toxicology, Trier University, Trier, Germany
| | - M Silva E Sousa
- Department of Environmental Toxicology, Trier University, Trier, Germany
| | - N Peter
- Department of Environmental Toxicology, Trier University, Trier, Germany
| | - F Sahli
- Dermatochemistry Laboratory, University of Strasbourg, Institute of Chemistry, CNRS UMR 7177, Strasbourg, France
| | - B Vileno
- POMAM Laboratory, University of Strasbourg, Institute of Chemistry, CNRS UMR 7177, Strasbourg, France.,French EPR Federation of Research, Réseau NAtional de Rpe interDisciplinaire (RENARD, Fédération IR-RPE CNRS #3443), Strasbourg, France
| | - S Kuresepi
- Dermatochemistry Laboratory, University of Strasbourg, Institute of Chemistry, CNRS UMR 7177, Strasbourg, France
| | - C Gourlaouen
- Laboratoire de Chimie Quantique, University of Strasbourg, Institute of Chemistry, CNRS UMR 7177, Strasbourg, France
| | - E Giménez-Arnau
- Dermatochemistry Laboratory, University of Strasbourg, Institute of Chemistry, CNRS UMR 7177, Strasbourg, France
| | - B Blömeke
- Department of Environmental Toxicology, Trier University, Trier, Germany
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Wu W, Peng G, Yang F, Zhang Y, Mu Z, Han X. Sulforaphane has a therapeutic effect in an atopic dermatitis murine model and activates the Nrf2/HO‑1 axis. Mol Med Rep 2019; 20:1761-1771. [PMID: 31257541 PMCID: PMC6625393 DOI: 10.3892/mmr.2019.10405] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 05/14/2019] [Indexed: 12/11/2022] Open
Abstract
Atopic dermatitis (AD), a chronic inflammatory skin disease, is characterized by intense itching and recurrent eczematous lesions. Sulforaphane is known to attenuate oxidative stress, and tissue or cell damage in cerebral ischemia, brain inflammation and intracerebral hemorrhage. In the present study, a 2,4‑dinitrochlorobenzene (DNCB)‑induced AD mouse model was developed, and ear thickness, dermatitis score, eosinophil count, mast cell infiltration, and serum IgE levels were measured in DNCB‑induced AD and sulforaphane‑treated groups to demonstrate the therapeutic effects of sulforaphane. AD symptoms of DNCB‑induced mice were attenuated by sulforaphane treatment compared with those of negative control mice; furthermore, eosinophil count, mast cell infiltration and serum IgE levels were also reduced by sulforaphane treatment in DNCB‑induced AD mice. Western blot assays revealed that the expression levels of nuclear factor‑E2‑related factor 2 (Nrf2) and heme oxygenase-1 (HO‑1), which exhibit oxidation resistance, were increased by sulforaphane treatment in DNCB‑induced AD mice. The present study suggested that sulforaphane exerted a therapeutic effect in the AD mouse model through the activation of the Nrf2/HO‑1 axis as well as the suppression of Janus kinase 1/STAT3 signaling pathway.
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Affiliation(s)
- Wenqing Wu
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Ge Peng
- Atopy (Allergy) Research Center, Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo 1138642, Japan
| | - Fan Yang
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Yue Zhang
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Zhenzhen Mu
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Xiuping Han
- Department of Dermatology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
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Helou DG, Martin SF, Pallardy M, Chollet-Martin S, Kerdine-Römer S. Nrf2 Involvement in Chemical-Induced Skin Innate Immunity. Front Immunol 2019; 10:1004. [PMID: 31134077 PMCID: PMC6514534 DOI: 10.3389/fimmu.2019.01004] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 04/18/2019] [Indexed: 12/21/2022] Open
Abstract
Exposure to certain chemicals disturbs skin homeostasis. In particular, protein-reactive chemical contact sensitizers trigger an inflammatory immune response resulting in eczema and allergic contact dermatitis. Chemical sensitizers activate innate immune cells which orchestrate the skin immune response. This involves oxidative and inflammatory pathways. In parallel, the Nrf2/Keap1 pathway, a major ubiquitous regulator of cellular oxidative and electrophilic stress is activated in the different skin innate immune cells including epidermal Langerhans cells and dermal dendritic cells, but also in keratinocytes. In this context, Nrf2 shows a strong protective capacity through the downregulation of both the oxidative stress and inflammatory pathways. In this review we highlight the important role of Nrf2 in the control of the innate immune response of the skin to chemical sensitizers.
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Affiliation(s)
- Doumet Georges Helou
- Inflammation, Chimiokines et Immunopathologie, INSERM UMR996, University Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
| | - Stefan F Martin
- Allergy Research Group, Department of Dermatology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Marc Pallardy
- Inflammation, Chimiokines et Immunopathologie, INSERM UMR996, University Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
| | - Sylvie Chollet-Martin
- Inflammation, Chimiokines et Immunopathologie, INSERM UMR996, University Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.,UF Auto-immunité et Hypersensibilités, Hôpital Bichat, APHP, Paris, France
| | - Saadia Kerdine-Römer
- Inflammation, Chimiokines et Immunopathologie, INSERM UMR996, University Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
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Helou DG, Noël B, Gaudin F, Groux H, El Ali Z, Pallardy M, Chollet-Martin S, Kerdine-Römer S. Cutting Edge: Nrf2 Regulates Neutrophil Recruitment and Accumulation in Skin during Contact Hypersensitivity. THE JOURNAL OF IMMUNOLOGY 2019; 202:2189-2194. [DOI: 10.4049/jimmunol.1801065] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 02/07/2019] [Indexed: 12/22/2022]
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12
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Clouet E, Bechara R, Raffalli C, Damiens MH, Groux H, Pallardy M, Ferret PJ, Kerdine-Römer S. The THP-1 cell toolbox: a new concept integrating the key events of skin sensitization. Arch Toxicol 2019; 93:941-951. [PMID: 30806763 DOI: 10.1007/s00204-019-02416-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 02/14/2019] [Indexed: 11/30/2022]
Abstract
According to the current scientific consensus, one in vitro test is insufficient to cover the key events (KE) defined by the adverse outcome pathway (AOP) for skin sensitization. To address this issue we combined different end points in the same cell line to cover all KEs defined by the skin sensitization AOP. Since dendritic cells (DC) play a key role in the sensitization phase leading to the development of allergic contact dermatitis (ACD), we used THP-1 cells as a surrogate for DC. We measured ROS production and GSH depletion for KE1 (binding to proteins), Nrf2 activation pathway and gene expressions for KE2 (keratinocyte response), phenotype modifications using cell-surface markers and cytokine production for KE3 (DC activation), and T-cell proliferation for KE4 (T-cell activation). These measurements were performed using the THP-1 cell line and an original THP-1/T-cell co-culture system following exposure to a variety of chemicals, including irritant, non-sensitizers, and chemicals sensitizers (pro/prehaptens). Results showed that treatment with sensitizers such as cinnamaldehyde (100 µM) or methylisothiazolinone (150 µM) was able to trigger the three main key events (KE1, KE2, and KE3) of the sensitization phase of ACD in THP-1 cells. In addition, all sensitizers were able to induce T lymphocyte proliferation (KE4), while non-sensitizers and irritants did not. Our study shows for the first time that addressing the four main KE of skin sensitization AOP in a single cell line is an achievable task.
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Affiliation(s)
- Elodie Clouet
- Safety Assessment Department, Pierre Fabre Dermo Cosmétique, Toulouse, France.,UMR996-Inflammation, Chemokines and Immunopathology, INSERM, Univ Paris-Sud, Université Paris-Saclay, 92296, Châtenay-Malabry, France
| | - Rami Bechara
- UMR996-Inflammation, Chemokines and Immunopathology, INSERM, Univ Paris-Sud, Université Paris-Saclay, 92296, Châtenay-Malabry, France
| | - Chloé Raffalli
- UMR996-Inflammation, Chemokines and Immunopathology, INSERM, Univ Paris-Sud, Université Paris-Saclay, 92296, Châtenay-Malabry, France
| | - Marie-Hélène Damiens
- UMR996-Inflammation, Chemokines and Immunopathology, INSERM, Univ Paris-Sud, Université Paris-Saclay, 92296, Châtenay-Malabry, France
| | | | - Marc Pallardy
- UMR996-Inflammation, Chemokines and Immunopathology, INSERM, Univ Paris-Sud, Université Paris-Saclay, 92296, Châtenay-Malabry, France
| | | | - Saadia Kerdine-Römer
- UMR996-Inflammation, Chemokines and Immunopathology, INSERM, Univ Paris-Sud, Université Paris-Saclay, 92296, Châtenay-Malabry, France.
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13
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Dal Negro G, Eskes C, Belz S, Bertein C, Chlebus M, Corvaro M, Corvi R, Dhalluin S, Halder M, Harvey J, Hermann M, Hoffmann-Dörr S, Kilian K, Lambrigts D, Laroche C, Louhimies S, Mahony C, Manou I, McNamee P, Prieto P, Reid K, Roggen E, Schutte K, Stirling C, Uhlrich S, Weissenhorn R, Whelan M. One science-driven approach for the regulatory implementation of alternative methods: A multi-sector perspective. Regul Toxicol Pharmacol 2018; 99:33-49. [PMID: 30098372 DOI: 10.1016/j.yrtph.2018.08.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 08/05/2018] [Indexed: 12/28/2022]
Abstract
EU regulations call for the use of alternative methods to animal testing. During the last decade, an increasing number of alternative approaches have been formally adopted. In parallel, new 3Rs-relevant technologies and mechanistic approaches have increasingly contributed to hazard identification and risk assessment evolution. In this changing landscape, an EPAA meeting reviewed the challenges that different industry sectors face in the implementation of alternative methods following a science-driven approach. Although clear progress was acknowledged in animal testing reduction and refinement thanks to an integration of scientifically robust approaches, the following challenges were identified: i) further characterization of toxicity pathways; ii) development of assays covering current scientific gaps, iii) better characterization of links between in vitro readouts and outcome in the target species; iv) better definition of alternative method applicability domains, and v) appropriate implementation of the available approaches. For areas having regulatory adopted alternative methods (e.g., vaccine batch testing), harmonised acceptance across geographical regions was considered critical for broader application. Overall, the main constraints to the application of non-animal alternatives are the still existing gaps in scientific knowledge and technological limitations. The science-driven identification of most appropriate methods is key for furthering a multi-sectorial decrease in animal testing.
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Affiliation(s)
- Gianni Dal Negro
- GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom
| | - Chantra Eskes
- SeCAM Services and Consultation on Alternative Methods, Via Campagnora 1, 6983, Magliaso, Switzerland.
| | - Susanne Belz
- European Commission, Joint Research Centre (JRC), Via E. Fermi 2749, 21017, Ispra, Italy
| | | | - Magda Chlebus
- European Federation of Pharmaceutical Industries and Associations (EFPIA), Rue du Trône 108, 1050, Brussels, Belgium
| | - Marco Corvaro
- ECPA - the European Crop Protection Association, 6 Avenue E. Van Nieuwenhuyse, 1160, Brussels, Belgium
| | - Raffaella Corvi
- European Commission, Joint Research Centre (JRC), Via E. Fermi 2749, 21017, Ispra, Italy
| | - Stephane Dhalluin
- L'Oréal Research & Innovation, 9 rue Pierre Dreyfus, 92110, Clichy, France
| | - Marlies Halder
- European Commission, Joint Research Centre (JRC), Via E. Fermi 2749, 21017, Ispra, Italy
| | - Jim Harvey
- GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom
| | - Martina Hermann
- Henkel AG & Co. KGaA, Henkelstr. 67, 40589, Duesseldorf, Germany
| | | | - Karin Kilian
- European Commission, Directorate General for the Environment (DG ENV), Brussels, Belgium
| | - Denis Lambrigts
- GlaxoSmithKline Vaccines, 20 Avenue Fleming, 1300, Wavre, Belgium
| | - Charles Laroche
- European Partnership for Alternative Approaches to Animal Testing (EPAA), Av. Herrmann-Debroux 40, 1160, Brussels, Belgium
| | - Susanna Louhimies
- European Commission, Directorate General for the Environment (DG ENV), Brussels, Belgium
| | - Catherine Mahony
- The Procter & Gamble Company, Whitehall Lane, Egham, Surrey TW20 9NW, United Kingdom
| | - Irene Manou
- European Partnership for Alternative Approaches to Animal Testing (EPAA), Av. Herrmann-Debroux 40, 1160, Brussels, Belgium
| | - Pauline McNamee
- The Procter & Gamble Company, Whitehall Lane, Egham, Surrey TW20 9NW, United Kingdom
| | - Pilar Prieto
- European Commission, Joint Research Centre (JRC), Via E. Fermi 2749, 21017, Ispra, Italy
| | - Kirsty Reid
- European Federation of Pharmaceutical Industries and Associations (EFPIA), Rue du Trône 108, 1050, Brussels, Belgium
| | - Erwin Roggen
- 3Rs Management and Consulting, Asavænget 14, 2800, Kongens Lyngby, Denmark
| | - Katrin Schutte
- European Commission, Directorate General for the Environment (DG ENV), Brussels, Belgium
| | | | - Sylvie Uhlrich
- Sanofi Pasteur, 1541 Av. Marcel Merieux, 69280, Marcy l'Etoile, France
| | - Renate Weissenhorn
- European Commission, Directorate General for Internal Market, Industry, Enterpreneurship and SME, Brussels, Belgium
| | - Maurice Whelan
- European Commission, Joint Research Centre (JRC), Via E. Fermi 2749, 21017, Ispra, Italy
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14
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Raffalli C, Clouet E, Kuresepi S, Damiens MH, Lepoittevin JP, Pallardy M, Ferret PJ, Giménez-Arnau E, Kerdine-Römer S. Editor’s Highlight: Fragrance Allergens Linalool and Limonene Allylic Hydroperoxides in Skin Allergy: Mechanisms of Action Focusing on Transcription Factor Nrf2. Toxicol Sci 2017; 161:139-148. [DOI: 10.1093/toxsci/kfx207] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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15
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Sullivan KM, Enoch SJ, Ezendam J, Sewald K, Roggen EL, Cochrane S. An Adverse Outcome Pathway for Sensitization of the Respiratory Tract by Low-Molecular-Weight Chemicals: Building Evidence to Support the Utility ofIn VitroandIn SilicoMethods in a Regulatory Context. ACTA ACUST UNITED AC 2017. [DOI: 10.1089/aivt.2017.0010] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Kristie M. Sullivan
- Physicians Committee for Responsible Medicine, Washington, District of Columbia
| | - Steven J. Enoch
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, England
| | - Janine Ezendam
- National Institute for Public Health and the Environment (RIVM), Centre for Health Protection, Bilthoven, The Netherlands
| | - Katherina Sewald
- Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany
| | - Erwin L. Roggen
- 3Rs Management & Consulting ApS (3RsMC ApS), Lyngby, Denmark
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16
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Pallardy MJ, Turbica I, Biola-Vidamment A. Why the Immune System Should Be Concerned by Nanomaterials? Front Immunol 2017; 8:544. [PMID: 28555135 PMCID: PMC5431153 DOI: 10.3389/fimmu.2017.00544] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 04/24/2017] [Indexed: 12/14/2022] Open
Abstract
Particles possess huge specific surface area and therefore nanomaterials exhibit unique characteristics, such as special physical properties and chemical hyper-reactivity, which make them particularly attractive but also raise numerous questions concerning their safety. Interactions of nanomaterials with the immune system can potentially lead to immunosuppression, hypersensitivity (allergy), immunogenicity and autoimmunity, involving both innate and adaptive immune responses. Inherent physical and chemical NP characteristics may influence their immunotoxicity, i.e., the adverse effects that can result from exposure. This review will focus on the possible interaction of nanomaterials including protein aggregates with the innate immune system with specific emphasis on antigen-presenting cells, i.e., dendritic cells, macrophages and monocytes.
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Affiliation(s)
- Marc J Pallardy
- "Inflammation, Chimiokines and Immunopathology", INSERM UMR 996, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
| | - Isabelle Turbica
- "Inflammation, Chimiokines and Immunopathology", INSERM UMR 996, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
| | - Armelle Biola-Vidamment
- "Inflammation, Chimiokines and Immunopathology", INSERM UMR 996, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
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17
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El Ali Z, Deloménie C, Botton J, Pallardy M, Kerdine-Römer S. Dendritic cells' death induced by contact sensitizers is controlled by Nrf2 and depends on glutathione levels. Toxicol Appl Pharmacol 2017; 322:41-50. [DOI: 10.1016/j.taap.2017.02.014] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2016] [Revised: 01/31/2017] [Accepted: 02/16/2017] [Indexed: 12/17/2022]
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18
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Mathers AR, Carey CD, Killeen ME, Diaz-Perez JA, Salvatore SR, Schopfer FJ, Freeman BA, Falo LD. Electrophilic nitro-fatty acids suppress allergic contact dermatitis in mice. Allergy 2017; 72:656-664. [PMID: 27718238 DOI: 10.1111/all.13067] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND Reactions between nitric oxide (NO), nitrite (NO2-), and unsaturated fatty acids give rise to electrophilic nitro-fatty acids (NO2 -FAs), such as nitro oleic acid (OA-NO2 ) and nitro linoleic acid (LNO2 ). Endogenous electrophilic fatty acids (EFAs) mediate anti-inflammatory responses by modulating metabolic and inflammatory signal transduction reactions. Hence, there is considerable interest in employing NO2 -FAs and other EFAs for the prevention and treatment of inflammatory disorders. Thus, we sought to determine whether OA-NO2 , an exemplary nitro-fatty acid, has the capacity to inhibit cutaneous inflammation. METHODS We evaluated the effect of OA-NO2 on allergic contact dermatitis (ACD) using an established model of contact hypersensitivity in C57Bl/6 mice utilizing 2,4-dinitrofluorobenzene as the hapten. RESULTS We found that subcutaneous (SC) OA-NO2 injections administered 18 h prior to sensitization and elicitation suppresses ACD in both preventative and therapeutic models. In vivo SC OA-NO2 significantly inhibits pathways that lead to inflammatory cell infiltration and the production of inflammatory cytokines in the skin. Moreover, OA-NO2 is capable of enhancing regulatory T-cell activity. Thus, OA-NO2 treatment results in anti-inflammatory effects capable of inhibiting ACD by inducing immunosuppressive responses. CONCLUSION Overall, these results support the development of OA-NO2 as a promising therapeutic for ACD and provides new insights into the role of electrophilic fatty acids in the control of cutaneous immune responses potentially relevant to a broad range of allergic and inflammatory skin diseases.
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Affiliation(s)
- A. R. Mathers
- Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh PA USA
- Department of Immunology; University of Pittsburgh School of Medicine; Pittsburgh PA USA
| | - C. D. Carey
- Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh PA USA
| | - M. E. Killeen
- Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh PA USA
| | - J. A. Diaz-Perez
- Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh PA USA
| | - S. R. Salvatore
- Department of Pharmacology and Chemical Biology; University of Pittsburgh School of Medicine; Pittsburgh PA USA
| | - F. J. Schopfer
- Department of Pharmacology and Chemical Biology; University of Pittsburgh School of Medicine; Pittsburgh PA USA
| | - B. A. Freeman
- Department of Pharmacology and Chemical Biology; University of Pittsburgh School of Medicine; Pittsburgh PA USA
| | - L. D. Falo
- Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh PA USA
- Department of Bioengineering; University of Pittsburgh School of Medicine; Pittsburgh PA USA
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19
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Natsch A, Emter R. Reaction Chemistry to Characterize the Molecular Initiating Event in Skin Sensitization: A Journey to Be Continued. Chem Res Toxicol 2016; 30:315-331. [DOI: 10.1021/acs.chemrestox.6b00365] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Andreas Natsch
- Biosciences, Givaudan Schweiz AG, Ueberlandstrasse 138, CH-8600 Duebendorf, Switzerland
| | - Roger Emter
- Biosciences, Givaudan Schweiz AG, Ueberlandstrasse 138, CH-8600 Duebendorf, Switzerland
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20
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Zwicker P, Schultze N, Niehs S, Methling K, Wurster M, Albrecht D, Bernhardt J, Wachlin G, Lalk M, Lindequist U, Haertel B. A proteomic approach for the identification of immunotoxic properties of Tulipalin A. Proteomics 2016; 16:2997-3008. [DOI: 10.1002/pmic.201600130] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 09/23/2016] [Accepted: 09/28/2016] [Indexed: 01/13/2023]
Affiliation(s)
- Paula Zwicker
- Institute of Pharmacy, Pharmaceutical Biology; Ernst-Moritz-Arndt-University; Greifswald Germany
| | - Nadin Schultze
- Institute of Pharmacy, Pharmaceutical Biology; Ernst-Moritz-Arndt-University; Greifswald Germany
| | - Sarah Niehs
- Institute of Biochemistry, Biochemistry of Metabolism/Metabolomics; Ernst-Moritz-Arndt-University; Greifswald Germany
| | - Karen Methling
- Institute of Biochemistry, Biochemistry of Metabolism/Metabolomics; Ernst-Moritz-Arndt-University; Greifswald Germany
| | - Martina Wurster
- Institute of Biochemistry, Biochemistry of Metabolism/Metabolomics; Ernst-Moritz-Arndt-University; Greifswald Germany
| | - Dirk Albrecht
- Institute of Microbiology, Microbial Physiology and Molecular Biology; Ernst-Moritz-Arndt-University; Greifswald Germany
| | - Jörg Bernhardt
- Institute of Microbiology, Microbial Physiology and Molecular Biology; Ernst-Moritz-Arndt-University; Greifswald Germany
| | - Gerhild Wachlin
- Institute of Microbiology, Microbial Physiology and Molecular Biology; Ernst-Moritz-Arndt-University; Greifswald Germany
| | - Michael Lalk
- Institute of Biochemistry, Biochemistry of Metabolism/Metabolomics; Ernst-Moritz-Arndt-University; Greifswald Germany
| | - Ulrike Lindequist
- Institute of Pharmacy, Pharmaceutical Biology; Ernst-Moritz-Arndt-University; Greifswald Germany
| | - Beate Haertel
- Institute of Pharmacy, Pharmaceutical Biology; Ernst-Moritz-Arndt-University; Greifswald Germany
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21
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Proteomics analysis of dendritic cell activation by contact allergens reveals possible biomarkers regulated by Nrf2. Toxicol Appl Pharmacol 2016; 313:170-179. [PMID: 27816475 DOI: 10.1016/j.taap.2016.11.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 10/28/2016] [Accepted: 11/01/2016] [Indexed: 12/17/2022]
Abstract
Allergic contact dermatitis is a widespread disease with high clinical relevance affecting approximately 20% of the general population. Typically, contact allergens are low molecular weight electrophilic compounds which can activate the Keap1/Nrf2 pathway. We performed a proteomics study to reveal possible biomarkers for dendritic cell (DC) activation by contact allergens and to further elucidate the role of Keap1/Nrf2 signaling in this process. We used bone marrow derived dendritic cells (BMDCs) of wild-type (nrf2+/+) and Nrf2 knockout (nrf2-/-) mice and studied their response against the model contact sensitizers 2,4-dinitrochlorobenzene (DNCB), cinnamaldehyde (CA) and nickel(II) sulfate by 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) in combination with electrospray ionization tandem mass spectrometry (ESI-MS/MS). Sodium dodecyl sulfate (SDS, 100μM) served as irritant control. While treatment with nickel(II) sulfate and SDS had only little effects, CA and DNCB led to significant changes in protein expression. We found 18 and 30 protein spots up-regulated in wild-type cells treated with 50 and 100μM CA, respectively. For 5 and 10μM DNCB, 32 and 37 spots were up-regulated, respectively. Almost all of these proteins were not differentially expressed in nrf2-/- BMDCs, indicating an Nrf2-dependent regulation. Among them proteins were detected which are involved in oxidative stress and heat shock responses, as well as in signal transduction or basic cellular pathways. The applied approach allowed us to differentiate between Nrf2-dependent and Nrf2-independent cellular biomarkers differentially regulated upon allergen-induced DC activation. The data presented might contribute to the further development of suitable in vitro testing methods for chemical-mediated sensitization.
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22
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Espinasse MA, Hajage D, Montravers P, Piednoir P, Dufour G, Tubach F, Granger V, de Chaisemartin L, Noël B, Pallardy M, Chollet-Martin S, Biola-Vidamment A. Neutrophil expression of glucocorticoid-induced leucine zipper (GILZ) anti-inflammatory protein is associated with acute respiratory distress syndrome severity. Ann Intensive Care 2016; 6:105. [PMID: 27807817 PMCID: PMC5093102 DOI: 10.1186/s13613-016-0210-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Accepted: 10/24/2016] [Indexed: 12/13/2022] Open
Abstract
Background Glucocorticoid-induced leucine zipper (GILZ) is a potent anti-inflammatory protein involved in neutrophil apoptosis and the resolution of inflammation. Given the numerous pathophysiologic roles of neutrophils in the acute respiratory distress syndrome (ARDS), we postulated that neutrophil GILZ expression might be induced during ARDS, to modulate the inflammatory process and participate in lung repair. Methods This single-center, prospective, observational cohort study took place in the surgical intensive care unit of Bichat Hospital (Paris, France) and involved 17 ARDS patients meeting the Berlin criteria at inclusion, and 14 ventilated controls without ARDS. Serial blood samples were obtained every 2 days until extubation or death (from 1 to 9 samples per patient). GILZ protein and gene expression was quantified in blood neutrophils, along with markers of inflammation (CRP, extracellular DNA) or its resolution (Annexin A1). Results Neutrophil GILZ expression was detected at the transcriptional and/or translational level in 9/17 ARDS patients (in particular 7/10 severe ARDS) and in 2/14 ventilated controls. The highest mRNA levels were observed in the most severely ill patients (p < 0.028). GILZ was expressed in about ¾ of the corticosteroid-treated patients and its expression could also occur independently of corticosteroids, suggesting that inflammatory signals may also induce neutrophil GILZ expression in vivo. Conclusions In this pilot study, we show for the first time that blood neutrophils from patients with ARDS can express GILZ, in keeping with an anti-inflammatory and regulatory endogenous role of GILZ in humans. Contrary to some markers of inflammation or its resolution, the levels of gilz gene expression were related to ARDS severity.
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Affiliation(s)
- Marie-Alix Espinasse
- INSERM UMR-996 - Inflammation, Chemokines and Immunopathology, Univ Paris-Sud, Faculté de pharmacie, Université Paris-Saclay, 5 rue JB Clément, 92296, Châtenay-Malabry Cedex, France
| | - David Hajage
- Département d'Epidémiologie et Recherche Clinique, Assistance Publique-Hôpitaux de Paris Hôpital Bichat, INSERM, CIE 801, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Philippe Montravers
- Département d'Anesthésie-Réanimation, Hôpital Bichat-Claude Bernard, AP-HP, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Pascale Piednoir
- Département d'Anesthésie-Réanimation, Hôpital Bichat-Claude Bernard, AP-HP, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Guillaume Dufour
- Département d'Anesthésie-Réanimation, Hôpital Bichat-Claude Bernard, AP-HP, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Florence Tubach
- Département d'Epidémiologie et Recherche Clinique, Assistance Publique-Hôpitaux de Paris Hôpital Bichat, INSERM, CIE 801, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Vanessa Granger
- INSERM UMR-996 - Inflammation, Chemokines and Immunopathology, Univ Paris-Sud, Faculté de pharmacie, Université Paris-Saclay, 5 rue JB Clément, 92296, Châtenay-Malabry Cedex, France.,Laboratoire d'immunologie, «Autoimmunité et hypersensibilités», Hôpital Bichat-Claude Bernard, AP-HP, Paris, France
| | - Luc de Chaisemartin
- INSERM UMR-996 - Inflammation, Chemokines and Immunopathology, Univ Paris-Sud, Faculté de pharmacie, Université Paris-Saclay, 5 rue JB Clément, 92296, Châtenay-Malabry Cedex, France.,Laboratoire d'immunologie, «Autoimmunité et hypersensibilités», Hôpital Bichat-Claude Bernard, AP-HP, Paris, France
| | - Benoît Noël
- INSERM UMR-996 - Inflammation, Chemokines and Immunopathology, Univ Paris-Sud, Faculté de pharmacie, Université Paris-Saclay, 5 rue JB Clément, 92296, Châtenay-Malabry Cedex, France
| | - Marc Pallardy
- INSERM UMR-996 - Inflammation, Chemokines and Immunopathology, Univ Paris-Sud, Faculté de pharmacie, Université Paris-Saclay, 5 rue JB Clément, 92296, Châtenay-Malabry Cedex, France
| | - Sylvie Chollet-Martin
- INSERM UMR-996 - Inflammation, Chemokines and Immunopathology, Univ Paris-Sud, Faculté de pharmacie, Université Paris-Saclay, 5 rue JB Clément, 92296, Châtenay-Malabry Cedex, France.,Laboratoire d'immunologie, «Autoimmunité et hypersensibilités», Hôpital Bichat-Claude Bernard, AP-HP, Paris, France
| | - Armelle Biola-Vidamment
- INSERM UMR-996 - Inflammation, Chemokines and Immunopathology, Univ Paris-Sud, Faculté de pharmacie, Université Paris-Saclay, 5 rue JB Clément, 92296, Châtenay-Malabry Cedex, France.
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Crude Preparations of Helicobacter pylori Outer Membrane Vesicles Induce Upregulation of Heme Oxygenase-1 via Activating Akt-Nrf2 and mTOR-IκB Kinase-NF-κB Pathways in Dendritic Cells. Infect Immun 2016; 84:2162-2174. [PMID: 27185786 PMCID: PMC4962631 DOI: 10.1128/iai.00190-16] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 05/06/2016] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori sheds outer membrane vesicles (OMVs) that contain many surface elements of bacteria. Dendritic cells (DCs) play a major role in directing the nature of adaptive immune responses against H. pylori, and heme oxygenase-1 (HO-1) has been implicated in regulating function of DCs. In addition, HO-1 is important for adaptive immunity and the stress response. Although H. pylori-derived OMVs may contribute to the pathogenesis of H. pylori infection, responses of DCs to OMVs have not been elucidated. In the present study, we investigated the role of H. pylori-derived crude OMVs in modulating the expression of HO-1 in DCs. Exposure of DCs to crude H. pylori OMVs upregulated HO-1 expression. Crude OMVs obtained from a cagA-negative isogenic mutant strain induced less HO-1 expression than OMVs obtained from a wild-type strain. Crude H. pylori OMVs activated signals of transcription factors such as NF-κB, AP-1, and Nrf2. Suppression of NF-κB or Nrf2 resulted in significant attenuation of crude OMV-induced HO-1 expression. Crude OMVs increased the phosphorylation of Akt and downstream target molecules of mammalian target of rapamycin (mTOR), such as S6 kinase 1 (S6K1). Suppression of Akt resulted in inhibition of crude OMV-induced Nrf2-dependent HO-1 expression. Furthermore, suppression of mTOR was associated with inhibition of IκB kinase (IKK), NF-κB, and HO-1 expression in crude OMV-exposed DCs. These results suggest that H. pylori-derived OMVs regulate HO-1 expression through two different pathways in DCs, Akt-Nrf2 and mTOR–IKK–NF-κB signaling. Following this induction, increased HO-1 expression in DCs may modulate inflammatory responses in H. pylori infection.
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Debeuckelaere C, Berl V, Elbayed K, Moussallieh FM, Namer IJ, Lepoittevin JP. Matrix Effect of Human Reconstructed Epidermis on the Chemoselectivity of a Skin Sensitizing α-Methylene-γ-Butyrolactone: Consequences for the Development of in Chemico Alternative Methods. Chem Res Toxicol 2015; 28:2192-8. [DOI: 10.1021/acs.chemrestox.5b00363] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Camille Debeuckelaere
- Institute
of Chemistry, CNRS UMR 7177 and University of Strasbourg, 4 rue
Blaise Pascal, 67081 Strasbourg, France
| | - Valérie Berl
- Institute
of Chemistry, CNRS UMR 7177 and University of Strasbourg, 4 rue
Blaise Pascal, 67081 Strasbourg, France
| | - Karim Elbayed
- Institute
of Chemistry, CNRS UMR 7177 and University of Strasbourg, 4 rue
Blaise Pascal, 67081 Strasbourg, France
- Laboratoire
des sciences de l’ingénieur, de l’informatique
et de l’imagerie (ICube), CNRS UMR 7357 and University of Strasbourg, 4 rue Blaise Pascal, 67081 Strasbourg, France
| | - François-Marie Moussallieh
- Institute
of Chemistry, CNRS UMR 7177 and University of Strasbourg, 4 rue
Blaise Pascal, 67081 Strasbourg, France
- Laboratoire
des sciences de l’ingénieur, de l’informatique
et de l’imagerie (ICube), CNRS UMR 7357 and University of Strasbourg, 4 rue Blaise Pascal, 67081 Strasbourg, France
| | - Izzie-Jacques Namer
- Laboratoire
des sciences de l’ingénieur, de l’informatique
et de l’imagerie (ICube), CNRS UMR 7357 and University of Strasbourg, 4 rue Blaise Pascal, 67081 Strasbourg, France
| | - J.-P. Lepoittevin
- Institute
of Chemistry, CNRS UMR 7177 and University of Strasbourg, 4 rue
Blaise Pascal, 67081 Strasbourg, France
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25
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Schäfer M, Werner S. Nrf2--A regulator of keratinocyte redox signaling. Free Radic Biol Med 2015; 88:243-252. [PMID: 25912479 DOI: 10.1016/j.freeradbiomed.2015.04.018] [Citation(s) in RCA: 128] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Revised: 04/10/2015] [Accepted: 04/13/2015] [Indexed: 01/12/2023]
Abstract
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.
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Affiliation(s)
- Matthias Schäfer
- Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland.
| | - Sabine Werner
- Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology, 8093 Zurich, Switzerland.
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26
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Espinasse MA, Pépin A, Virault-Rocroy P, Szely N, Chollet-Martin S, Pallardy M, Biola-Vidamment A. Glucocorticoid-Induced Leucine Zipper Is Expressed in Human Neutrophils and Promotes Apoptosis through Mcl-1 Down-Regulation. J Innate Immun 2015; 8:81-96. [PMID: 26384220 DOI: 10.1159/000439052] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 07/29/2015] [Indexed: 01/19/2023] Open
Abstract
Glucocorticoid-induced leucine zipper (GILZ) is a potent anti-inflammatory protein, the expression of which is mainly induced by glucocorticoids (GCs) in haematopoietic cells. GILZ regulates signal transduction pathways of inflammation and plays a role in cell survival. The objective of this study was to evaluate the expression and mechanisms of action of GILZ in the apoptosis of human neutrophils. GILZ expression was induced by GCs in human neutrophils, enhanced upon phosphatidylinositol 3-kinase inhibition and resulted in apoptosis amplification. We then stably transfected PLB-985 cells with the human gilz gene and differentiated both control and GILZ-overexpressing clones in neutrophil-like cells. GILZ overexpression in PLB-985 cells led to an exacerbated apoptosis, associated with caspase-3, caspase-9 and caspase-8 activations, and a loss of mitochondrial potential, suggesting that GILZ-induced apoptosis used the mitochondrial pathway. The expression of BH3 interacting domain death agonist, Bcl-2 interacting mediator of cell death, annexin-A1 and Bcl-2-associated X was not affected in PLB-985-GILZ clones, but phosphorylation and subsequent proteasomal degradation of myeloid cell leukemia-1 (Mcl-1) were observed. Noteworthy, Mcl-1 phosphorylation was related to a significant and sustained activation of c-Jun N-terminal kinase (JNK) in PLB-985-GILZ clones. These results reveal GILZ to be a new actor in apoptosis regulation in neutrophil-like cells involving JNK and Mcl-1.
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Affiliation(s)
- Marie-Alix Espinasse
- UMR996 - Inflammation, Chemokines and Immunopathology, Inserm, Universitx00E9; Paris-Sud, Universitx00E9; Paris-Saclay, Chx00E2;tenay-Malabry, France
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27
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Reporter cell lines for skin sensitization testing. Arch Toxicol 2015; 89:1645-68. [DOI: 10.1007/s00204-015-1555-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 06/17/2015] [Indexed: 12/21/2022]
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28
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Krutz NL, Hennen J, Korb C, Schellenberger MT, Gerberick GF, Blömeke B. Activation of the Endoperoxide Ascaridole Modulates Its Sensitizing Capacity. Toxicol Sci 2015; 147:515-23. [DOI: 10.1093/toxsci/kfv148] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
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29
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Wong CL, Ghassabian S, Smith MT, Lam AL. In vitro methods for hazard assessment of industrial chemicals - opportunities and challenges. Front Pharmacol 2015; 6:94. [PMID: 25999858 PMCID: PMC4419653 DOI: 10.3389/fphar.2015.00094] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 04/16/2015] [Indexed: 11/13/2022] Open
Abstract
Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity immune reaction mediated by T-lymphocytes as a result of repeated exposure of an allergen primarily on skin. ACD accounts for up to 95% of occupational skin diseases, with epoxy resins implicated as one of the most common causes of ACD. Efficient high-throughput in vitro screening for accurate identification of compounds and materials that may pose hazardous risks in the workplace is crucial. At present, the murine local lymph node assay is the 'method of choice' for predicting the sensitizing potency of contact allergens. As the 3Rs principles of reduction, refinement, and replacement in animal testing has gained political and economic momentum, several in vitro screening methods have been developed for identifying potential contact allergens. To date, these latter methods have been utilized primarily to assess the skin sensitizing potential of the chemical components of cosmetic products with scant research attention as to the applicability of these methods to industrial chemicals, particularly epoxy resins. Herein we review the currently utilized in vitro methods and identify the knowledge gaps with regard to assessing the generalizability of in vitro screening methods for assessing the skin sensitizing potential of industrial chemicals.
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Affiliation(s)
- Chin Lin Wong
- Centre for Integrated Preclinical Drug Development, The University of QueenslandSt Lucia, QLD, Australia
- School of Pharmacy, The University of QueenslandWoolloongabba, QLD, Australia
| | - Sussan Ghassabian
- Centre for Integrated Preclinical Drug Development, The University of QueenslandSt Lucia, QLD, Australia
| | - Maree T. Smith
- Centre for Integrated Preclinical Drug Development, The University of QueenslandSt Lucia, QLD, Australia
- School of Pharmacy, The University of QueenslandWoolloongabba, QLD, Australia
| | - Ai-Leen Lam
- Centre for Integrated Preclinical Drug Development, The University of QueenslandSt Lucia, QLD, Australia
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30
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Gęgotek A, Skrzydlewska E. The role of transcription factor Nrf2 in skin cells metabolism. Arch Dermatol Res 2015; 307:385-96. [PMID: 25708189 PMCID: PMC4469773 DOI: 10.1007/s00403-015-1554-2] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Revised: 02/06/2015] [Accepted: 02/12/2015] [Indexed: 12/22/2022]
Abstract
Skin, which is a protective layer of the body, is in constant contact with physical and chemical environmental factors. Exposure of the skin to highly adverse conditions often leads to oxidative stress. Moreover, it has been observed that skin cells are also exposed to reactive oxygen species generated during cell metabolism particularly in relation to the synthesis of melanin or the metabolism in immune system cells. However, skin cells have special features that protect them against oxidative modifications including transcription factor Nrf2, which is responsible for the transcription of the antioxidant protein genes such as antioxidant enzymes, small molecular antioxidant proteins or interleukins, and multidrug response protein. In the present study, the mechanisms of Nrf2 activation have been compared in the cells forming the various layers of the skin: keratinocytes, melanocytes, and fibroblasts. The primary mechanism of control of Nrf2 activity is its binding by cytoplasmic inhibitor Keap1, while cells have also other controlling mechanisms, such as phosphorylation of Nrf2 and modifications of its activators (e.g., Maf, IKKβ) or inhibitors (e.g., Bach1, caveolae, TGF-β). Moreover, there are a number of drugs (e.g., ketoconazole) used in the pharmacotherapy of skin diseases based on the activation of Nrf2, but they may also induce oxidative stress. Therefore, it is important to look for compounds that cause a selective activation of Nrf2 particularly natural substances such as curcumin, sulforaphane, or extracts from the broccoli leaves without side effects. These findings could be helpful in the searching for new drugs for people with vitiligo or even melanoma.
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Affiliation(s)
- Agnieszka Gęgotek
- Departments of Analytical Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15-222, Bialystok, Poland,
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31
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Harrison R. 2013 Lush Science Prize. Altern Lab Anim 2015; 42:395-402. [PMID: 25635648 DOI: 10.1177/026119291404200609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The annual Lush Science Prize is designed to reward outstanding contributions to 21st Century Toxicology Research. A Background Paper is prepared each year prior to the judging process, in order to provide the judging panel with a brief overview of current developments in the field of Replacement alternatives, particularly those relevant to the concept of toxicity pathways. The Background Paper includes information on some key institutional developments in the area--such as the OECD's Adverse Outcome Pathway Project, the Hamner Institute's work, and the Human Toxome Project, and on the phenomenon of collaborative computer systems relevant to the field. From the literature review that was also performed as part of the background research, the two papers receiving the highest score were recommended for consideration by the judges for the 2013 Science Prize.
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32
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Stiefel C, Schwack W. Photoprotection in changing times - UV filter efficacy and safety, sensitization processes and regulatory aspects. Int J Cosmet Sci 2014; 37:2-30. [DOI: 10.1111/ics.12165] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 09/20/2014] [Indexed: 12/14/2022]
Affiliation(s)
- C. Stiefel
- Institute of Food Chemistry; University of Hohenheim; Garbenstrasse 28 70599 Stuttgart Germany
| | - W. Schwack
- Institute of Food Chemistry; University of Hohenheim; Garbenstrasse 28 70599 Stuttgart Germany
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33
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Parkinson E, Boyd P, Aleksic M, Cubberley R, O'Connor D, Skipp P. Stable isotope labeling method for the investigation of protein haptenation by electrophilic skin sensitizers. Toxicol Sci 2014; 142:239-49. [PMID: 25145658 DOI: 10.1093/toxsci/kfu168] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The risk of contact sensitization is a major consideration in the development of new formulations for personal care products. However, developing a mechanistic approach for non-animal risk assessment requires further understanding of haptenation of skin proteins by sensitizing chemicals, which is the molecular initiating event causative of skin sensitization. The non-stoichiometric nature of protein haptenation results in relatively low levels of modification, often of low abundant proteins, presenting a major challenge for their assignment in complex biological matrices such as skin. Instrumental advances over the last few years have led to a considerable increase in sensitivity of mass spectrometry (MS) techniques. We have combined these advancements with a novel dual-labeling/LC-MS(E) approach to provide an in-depth direct comparison of human serum albumin (HSA), 2,4-dinitro-1-chlorobenzene (DNCB), 5-chloro-2-methyl-4-isothiazolin-3-one (MCI), trans-cinnamaldehyde, and 6-methyl coumarin. These data have revealed novel insights into the differences in protein haptenation between sensitizers with different reaction mechanisms and sensitizing potency; the extreme sensitizers DNCB and MCI were shown to modify a greater number of nucleophilic sites than the moderate sensitizer cinnamaldehyde; and the weak/non-sensitizer 6-methyl coumarin was restricted to only a single nucleophilic residue within HSA. The evaluation of this dual labeling/LC-MS(E) approach using HSA as a model protein has also demonstrated that this strategy could be applied to studying global haptenation in complex mixtures of skin-related proteins by different chemicals.
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Affiliation(s)
- Erika Parkinson
- Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
| | - Pete Boyd
- Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
| | - Maja Aleksic
- Safety and Environmental Assurance Centre, Unilever, Colworth Science Park, Sharnbrook, MK44 1LQ, UK
| | - Richard Cubberley
- Safety and Environmental Assurance Centre, Unilever, Colworth Science Park, Sharnbrook, MK44 1LQ, UK
| | - David O'Connor
- Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, SIP Suzhou, Jiangsu Province 215123, China
| | - Paul Skipp
- Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
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34
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White AG, Wolsic CL, Campbell KL, Lavergne SN. Canine progenitor epidermal keratinocytes express various inflammatory markers, including interleukin-8 and CD40, which are affected by certain antibiotics. Vet Dermatol 2014; 25:493-502, e81-2. [DOI: 10.1111/vde.12164] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/28/2014] [Indexed: 12/24/2022]
Affiliation(s)
- Amelia G. White
- Veterinary Clinical Medicine; College of Veterinary Medicine; University of Illinois; 1008 W Hazelwood Drive Urbana IL 61802 USA
| | - Cassandra L. Wolsic
- Comparative Biosciences; College of Veterinary Medicine; University of Illinois; 2001 South Lincoln Avenue Urbana IL 61802 USA
| | - Karen L. Campbell
- Veterinary Clinical Medicine; College of Veterinary Medicine; University of Illinois; 1008 W Hazelwood Drive Urbana IL 61802 USA
| | - Sidonie N. Lavergne
- Comparative Biosciences; College of Veterinary Medicine; University of Illinois; 2001 South Lincoln Avenue Urbana IL 61802 USA
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35
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Gonçalo M, Martins J, Silva A, Neves B, Figueiredo A, Cruz T, Lopes C. Systemic drugs inducing non-immediate cutaneous adverse reactions and contact sensitizers evoke similar responses in THP-1 cells. J Appl Toxicol 2014; 35:398-406. [PMID: 25091725 DOI: 10.1002/jat.3033] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 05/03/2014] [Accepted: 05/05/2014] [Indexed: 12/22/2022]
Abstract
Contact sensitizers induce phenotypic and functional changes in dendritic cells (DC) that enhance their antigen-presenting capacity and, ultimately, modulate the T cell response. To evaluate if there is a similar effect of drugs causing T-cell-mediated cutaneous adverse drug reactions (CADR), we studied the in vitro effect of drugs on THP-1 cells, a cell line widely used to evaluate the early molecular and cellular events triggered by contact sensitizers. The effect of allopurinol, oxypurinol, ampicillin, amoxicillin, carbamazepine and sodium valproate, at EC30 concentrations, was evaluated on p38 MAPK activation, by Western Blot, and on the expression of genes coding for DC maturation markers, pro-inflammatory cytokine/chemokines and hemeoxygenase 1 (HMOX1), by real-time RT-PCR. Results were compared with lipopolysaccharide (LPS), a DC maturation stimulus, and the strong contact sensitizer, 1-fluoro-2,4-dinitrobenzene (DNFB). All drugs studied significantly upregulated HMOX1 gene transcription and all, except the anticonvulsants, also upregulated IL8. Allopurinol and oxypurinol showed the most intense effect, in a magnitude similar to DNFB and superior to betalactams. Transcription of CD40, IL12B and CXCL10 genes by drugs was more irregular. Moreover, like DNFB, all drugs activated p38 MAPK, although significantly only for oxypurinol. Like contact sensitizers, drugs that cause non-immediate CADR activate THP-1 cells in vitro, using different signalling pathways and affecting gene transcription with an intensity that may reflect the frequency and severity of the CADR they cause. Direct activation of antigen-presenting DC by systemic drugs may be an important early step in the pathophysiology of non-immediate CADR.
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Affiliation(s)
- Margarida Gonçalo
- Department of Dermatology, University Hospital and Faculty of Medicine, University of Coimbra, 3000-075, Coimbra, Portugal
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36
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Roggen EL. In VitroApproaches for Detection of Chemical Sensitization. Basic Clin Pharmacol Toxicol 2014; 115:32-40. [DOI: 10.1111/bcpt.12202] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 01/14/2014] [Indexed: 11/30/2022]
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37
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Goebel C, Troutman J, Hennen J, Rothe H, Schlatter H, Gerberick GF, Blömeke B. Introduction of a methoxymethyl side chain into p-phenylenediamine attenuates its sensitizing potency and reduces the risk of allergy induction. Toxicol Appl Pharmacol 2013; 274:480-7. [PMID: 24333256 DOI: 10.1016/j.taap.2013.11.016] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Revised: 11/04/2013] [Accepted: 11/26/2013] [Indexed: 11/16/2022]
Abstract
The strong sensitizing potencies of the most important primary intermediates of oxidative hair dyes, p-phenylenediamine (PPD) and p-toluylenediamine (PTD, i.e. 2-methyl-PPD) are well established. They are considered as the key sensitizers in hair dye allergic contact dermatitis. While modification of their molecular structure is expected to alter their sensitizing properties, it may also impair their color performance. With introduction of a methoxymethyl side chain we found the primary intermediate 2-methoxymethyl-p-phenylenediamine (ME-PPD) with excellent hair coloring performance but significantly reduced sensitizing properties compared to PPD and PTD: In vitro, ME-PPD showed an attenuated innate immune response when analyzed for its protein reactivity and dendritic cell activation potential. In vivo, the effective concentration of ME-PPD necessary to induce an immune response 3-fold above vehicle control (EC3 value) in the local lymph node assay (LLNA) was 4.3%, indicating a moderate skin sensitizing potency compared to values of 0.1 and 0.17% for PPD and PTD, respectively. Finally, assessing the skin sensitizing potency of ME-PPD under consumer hair dye usage conditions through a quantitative risk assessment (QRA) indicated an allergy induction risk negligible compared to PPD or PTD.
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Affiliation(s)
- Carsten Goebel
- The Procter & Gamble Co., Central Product Safety and Communications, Darmstadt, Germany.
| | - John Troutman
- The Procter & Gamble Co., Central Product Safety, Cincinnati, OH, USA
| | - Jenny Hennen
- Dept. of Environmental Toxicology, Trier University, Trier, Germany
| | - Helga Rothe
- The Procter & Gamble Co., Central Product Safety and Communications, Darmstadt, Germany
| | - Harald Schlatter
- The Procter & Gamble Co., Central Product Safety and Communications, Darmstadt, Germany
| | - G Frank Gerberick
- The Procter & Gamble Co., Central Product Safety, Cincinnati, OH, USA
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