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1
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Tordjman L, Mashoudy KD, Czarnowicki T. Converging paths toward unified therapeutic approaches in atopic dermatitis, vitiligo, and alopecia areata. J Allergy Clin Immunol 2025:S0091-6749(25)00456-7. [PMID: 40274075 DOI: 10.1016/j.jaci.2025.04.016] [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: 11/18/2024] [Revised: 04/01/2025] [Accepted: 04/17/2025] [Indexed: 04/26/2025]
Abstract
Emerging evidence reveals significant epidemiologic, genetic, and immunologic connections between atopic dermatitis, vitiligo, and alopecia areata, challenging previously established notions of their distinct pathogenic and molecular signatures. Exploring these commonalities not only enhances our understanding of each disease's pathogenesis, but also supports the development of unified treatment strategies for these frequently co-occurring disorders. This review examines key immune players shared across the 3 conditions, including cytokines, immune cells, and signaling pathways. Building on these insights, we also evaluate a range of therapeutic options-ranging from treatments approved by the Food and Drug Administration to those currently in clinical trials-alongside proposed future therapeutic targets. This comprehensive approach aims to advance our management of these interconnected autoimmune and inflammatory disorders with greater precision.
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Affiliation(s)
- Lea Tordjman
- University of Miami Miller School of Medicine, Miami, Fla
| | | | - Tali Czarnowicki
- Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Fla.
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2
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Quaade AS, Litman T, Wang X, Becker C, McCauley BD, Sølberg JBK, Thyssen JP, Johansen JD. Transcriptomic profiling of chronic hand eczema skin reveals shared immune pathways and molecular drivers across subtypes. J Allergy Clin Immunol 2025; 155:1250-1263. [PMID: 39793713 DOI: 10.1016/j.jaci.2024.12.1091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 11/20/2024] [Accepted: 12/31/2024] [Indexed: 01/13/2025]
Abstract
BACKGROUND Chronic hand eczema (CHE) is a common skin disease with different subtypes, but knowledge of the molecular patterns associated with each subtype is limited. OBJECTIVE We sought to characterize the CHE transcriptome across subtypes. METHODS Using RNA sequencing, we studied the transcriptome of 220 full-thickness skin biopsy samples collected from palms, dorsa, and arms from 96 patients with CHE and/or atopic dermatitis (AD) and 32 healthy controls. The primary analysis focused on 16 healthy and 54 lesional CHE palm samples that were further stratified by AD status and unique etiology. Differentially expressed genes (DEGs) were identified across the cohort, and Ingenuity Pathway Analysis (IPA) was used for pathway analysis and upstream regulator prediction. RESULTS We identified anatomic site-specific transcriptomic variations, showing unique characteristics in both healthy and CHE-affected palm skin. In CHE palms, we identified 2333 DEGs versus healthy palms. Upregulated genes predominantly involved keratinocyte host inflammation and immune signaling, while downregulated genes were linked to lipid metabolism and epidermal barrier function. IPA revealed numerous activated proinflammatory pathways, dominated by TH1 and TH2. Key upstream regulators included type 1 (IFN-γ, TNF, STAT1, IL-2) and type 2 (IL-4) associated molecules, and IL-1β. Lesional palm signatures were broadly shared across CHE subtypes. No DEGs were found between allergic and irritant contact dermatitis CHE. Subtype-specific pathway and upstream regulator activity variations were noted. CONCLUSION The lesional CHE transcriptome is primarily shared among subtypes and is characterized by activation of several immune pathways, dominated by TH1 and TH2. Key shared upstream regulators were identified, highlighting potential universal therapeutic targets.
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Affiliation(s)
- Anna Sophie Quaade
- The National Allergy Research Centre, Department of Dermatology and Allergy, Copenhagen University Hospital, Herlev-Gentofte, Hellerup, Denmark.
| | - Thomas Litman
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Xing Wang
- Department of Medicine, Division of Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Christine Becker
- Department of Medicine, Division of Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Benjamin D McCauley
- Department of Medicine, Division of Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Julie Breinholt Kjær Sølberg
- The National Allergy Research Centre, Department of Dermatology and Allergy, Copenhagen University Hospital, Herlev-Gentofte, Hellerup, Denmark
| | - Jacob P Thyssen
- The National Allergy Research Centre, Copenhagen University Hospital, Herlev-Gentofte, Hellerup, Denmark
| | - Jeanne Duus Johansen
- The National Allergy Research Centre, Department of Dermatology and Allergy, Copenhagen University Hospital, Herlev-Gentofte, Hellerup, Denmark
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3
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Buttar PA, Mazhar MU, Khan JZ, Jamil M, Abid M, Tipu MK. Saccharomyces boulardii (CNCM I-745) ameliorates Ovalbumin-induced atopic dermatitis by modulating the NF-κB signaling in skin and colon. Arch Dermatol Res 2025; 317:500. [PMID: 40009233 DOI: 10.1007/s00403-025-04057-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 02/09/2025] [Accepted: 02/12/2025] [Indexed: 02/27/2025]
Abstract
Atopic dermatitis (AD) is a long-lasting allergic disorder characterized by itching, redness, swelling, dry skin, scaling, inflammation, and tissue damage. The exact cause of AD is still unknown. Steroid medications are frequently utilized in treating AD, but their prolonged use can result in complications. Multiple studies suggest probiotics may regulate the immune system, boost immune functionality, or reduce overactive immune responses. The current study investigated the anti-inflammatory, antioxidant, and immunomodulatory role of Saccharomyces boulardii in Ovalbumin (OVA)-induced AD in a murine model. Balb/c mice were sensitized and challenged with OVA to induce AD-like lesions. S. boulardii 1 × 109 CFU/ml/day/mice was orally administrated either as a pretreatment (administered 7 days before OVA induction and continued till day 28) or concurrent treatment (administered from day 1 and continued till day 28). Dexamethasone (5 mg/kg/day) was used as a standard treatment. S. boulardii alleviated the macroscopic and behavioral changes. Blood inflammatory cells were significantly reduced. Serum IgE levels were decreased. Oxidative stress and histopathological changes (epidermal/dermal thickness, inflammatory cells, collagen deposition) in skin tissue were improved. Similarly, the colon's antioxidant capacity and histological architecture were also maintained. Expression of proinflammatory cytokines like TNF-⍺ and IL-1β were significantly reduced in skin and colon tissue. The probiotic S. boulardii under study reduced inflammation by downregulating NF-κB signaling in both skin and colon tissue. This study provides a basis for a possible gut-skin axis, which can be targeted to relieve AD symptoms.
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Affiliation(s)
- Parveen Akhtar Buttar
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Muhammad Usama Mazhar
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Jehan Zeb Khan
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Maryam Jamil
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Muhammad Abid
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Muhammad Khalid Tipu
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
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4
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Tsoi L, Dong Y, Patrick M, Sarkar M, Zhang H, Bogle R, Zhang Z, Dand N, Paulsen M, Ljungman M, Betz RC, Petukhova L, Christiano A, Simpson M, Modlin R, Khanna D, Barker J, Budunova I, Gharaee-Kermani M, Billi A, Elder J, Kahlenberg JM, Gudjonsson J. IL-1 signaling enrichment in inflammatory skin disease loci with higher-risk allele frequencies in African ancestry. RESEARCH SQUARE 2025:rs.3.rs-5724270. [PMID: 39975900 PMCID: PMC11838759 DOI: 10.21203/rs.3.rs-5724270/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Inflammatory skin diseases (ISDs) exhibit varying prevalence across different ancestry background and geographical regions. Genetic research for complex ISDs has predominantly centered on European Ancestry (EurA) populations and genetic effects on immune cell responses but generally failed to consider contributions from other cell types in skin. Here, we utilized 273 genetic signals from seven different ISDs: acne, alopecia areata (AA), atopic dermatitis (AD), psoriasis, systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and vitiligo, to demonstrate enriched IL1 signaling in keratinocytes, particularly in signals with higher risk allele frequencies in the African ancestry. Using a combination of ATAC-seq, Bru-seq, and promoter capture Hi-C, we revealed potential regulatory mechanisms of the acne locus on chromosome 2q13. We further demonstrated differential responses in keratinocytes upon IL1β stimulation, including the pro-inflammatory mediators CCL5, IL36G, and CXCL8. Taken together, our findings highlight IL1 signaling in epidermal keratinocytes as a contributor to ancestry-related differences in ISDs.
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Affiliation(s)
| | | | | | | | | | - Rachael Bogle
- Department of Dermatology, INSERM 1098, Franche comté university, Besançon university hospital
| | | | | | | | | | | | | | | | | | - Robert Modlin
- University of California Los Angeles, David Geffen School of Medicine
| | | | | | | | | | | | - James Elder
- Department of Dermatology, University of Michigan, 1500 East Medical Center
| | - J Michelle Kahlenberg
- Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI, 48109, USA
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5
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Tandon R, Harder I, Stölzl D, Hübenthal M, Sander N, Hartmann J, Suhrkamp I, Fonfara M, Gerdes S, Weidinger S. Tralokinumab Treatment of Atopic Dermatitis Induces a Progressive Transcriptomic Response. J Invest Dermatol 2024:S0022-202X(24)03035-5. [PMID: 39733934 DOI: 10.1016/j.jid.2024.12.005] [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: 07/12/2024] [Revised: 11/05/2024] [Accepted: 12/03/2024] [Indexed: 12/31/2024]
Abstract
Atopic dermatitis is characterized by a complex epidermal barrier deficiency and exaggerated immune responses dominated by type 2 mechanisms with variable contributions of additional immune axes. IL-13 is overexpressed in atopic dermatitis skin and a key driver of both barrier dysfunction and inflammation. In this study, we prospectively studied the effects of IL-13 inhibition with tralokinumab on cutaneous transcriptome profiles using RNA sequencing of biopsies from 16 patients with moderate-to-severe atopic dermatitis obtained at baseline, week 2, and week 16. Tralokinumab therapy induced early and delayed expression changes and progressively shifted the transcriptomic profile of lesional toward nonlesional skin by modulating both genes associated with keratinocyte proliferation and differentiation, itch signaling, and downstream inflammatory responses. At week 16, 751 genes were still significantly dysregulated compared with those in healthy control skin, reinforcing the need for long-term immunomodulatory therapy of moderate-to-severe atopic dermatitis to achieve deep responses. The study was registered with ClinicalTrials.gov (NCT04556461).
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Affiliation(s)
- Rashmi Tandon
- Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Inken Harder
- Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Dora Stölzl
- Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Matthias Hübenthal
- Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Nicole Sander
- Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Jan Hartmann
- Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Ina Suhrkamp
- Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Melina Fonfara
- Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Sascha Gerdes
- Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Stephan Weidinger
- Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany.
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6
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Bucci P, Martínez-Navarrete M, Marti-Quijal FJ, José Guillot A, Barba FJ, Ferrer E, Cantero D, Muñoz R, Melero A. In vivo reduction of skin inflammation using ferulic acid-loaded lipid vesicles derived from Brewer's spent grain. Int J Pharm 2024; 666:124764. [PMID: 39332462 DOI: 10.1016/j.ijpharm.2024.124764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/04/2024] [Accepted: 09/24/2024] [Indexed: 09/29/2024]
Abstract
Breweŕs spent grain (BSG) is the main by-product of the brewing industry, and due to its rapid decomposition, it generates serious environmental problems such as malodors and greenhouse gases emissions. On the other hand, this lignocellulosic compound contains a large number of antioxidants, being ferulic acid (FA) the most abundant. FA is a powerful antioxidant molecule that has demonstrated significant protective effects on key components of the skin, including keratinocytes, fibroblasts, collagen, and elastin. FA inhibits melanogenesis, promotes angiogenesis and accelerates the wound healing although its use is limited by its rapid oxidation. In this study, different hydrolysis treatments (chemical, enzymatic and hydrothermal) were performed on BSG to obtain FA. Herein FA-loaded ultradeformable liposomes (ULs) were designed to improve their stability and in vivo performance. These nanosystems allow FA permeability through human skin, as proven by an ex vivo skin permeability assay using Franz diffusion cells. The toxicity and anti-inflammatory activity of the formulation has been investigated. The free form and 100 nm FA_ULs were evaluated. Cell viability was dose-dependent and provided optimal results for the treatment of inflammatory skin conditions in an in vivo Oxazolone-induced Delayed Type Hypersensitivity model using Swiss CD1 mice, demonstrated by the reduction of the inflammatory cytokines expression, ear thickness, bioluminescence and histological evaluation. These results pave the way for FA-based treatments of skin and inflammatory conditions.
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Affiliation(s)
- Paula Bucci
- Institute of Sustainable Processes, Department of Chemical Engineering and Environmental Technology, University of Valladolid, Dr. Mergelina s/n., Valladolid 47011, Spain.
| | - Miquel Martínez-Navarrete
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Avenida Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain
| | - Francisco J Marti-Quijal
- Research group in Innovative Technologies for Sustainable Food (ALISOST), Department of Preventive Medicine and Public Health, Food Science, Toxicology and Forensic Medicine, Faculty of Pharmacy and Food Sciences, Universitat de València, Avenida Vicent Andrés Estellés s/n, Burjassot, València 46100, Spain
| | - Antonio José Guillot
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Avenida Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain
| | - Francisco J Barba
- Research group in Innovative Technologies for Sustainable Food (ALISOST), Department of Preventive Medicine and Public Health, Food Science, Toxicology and Forensic Medicine, Faculty of Pharmacy and Food Sciences, Universitat de València, Avenida Vicent Andrés Estellés s/n, Burjassot, València 46100, Spain
| | - Emilia Ferrer
- Research group in Innovative Technologies for Sustainable Food (ALISOST), Department of Preventive Medicine and Public Health, Food Science, Toxicology and Forensic Medicine, Faculty of Pharmacy and Food Sciences, Universitat de València, Avenida Vicent Andrés Estellés s/n, Burjassot, València 46100, Spain
| | - Danilo Cantero
- The Institute of Bioeconomy. Calle Dr Mergelina S/N, Department of Chemical Engineering and Environmental Technology, University of Valladolid, Valladolid 47011, Spain
| | - Raúl Muñoz
- Institute of Sustainable Processes, Department of Chemical Engineering and Environmental Technology, University of Valladolid, Dr. Mergelina s/n., Valladolid 47011, Spain
| | - Ana Melero
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Avenida Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain
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7
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Martínez-Navarrete M, Guillot AJ, Lobita MC, Recio MC, Giner R, Aparicio-Blanco J, Montesinos MC, Santos HA, Melero A. Cyclosporin A-loaded dissolving microneedles for dermatitis therapy: Development, characterisation and efficacy in a delayed-type hypersensitivity in vivo model. Drug Deliv Transl Res 2024; 14:3404-3421. [PMID: 38472726 PMCID: PMC11499354 DOI: 10.1007/s13346-024-01542-9] [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] [Accepted: 02/07/2024] [Indexed: 03/14/2024]
Abstract
Several drugs can be used for treating inflammatory skin pathologies like dermatitis and psoriasis. However, for the management of chronic and long-term cases, topical administration is preferred over oral delivery since it prevents certain issues due to systemic side effects from occurring. Cyclosporin A (CsA) has been used for this purpose; however, its high molecular weight (1202 Da) restricts the diffusion through the skin structure. Here, we developed a nano-in-micro device combining lipid vesicles (LVs) and dissolving microneedle array patches (DMAPs) for targeted skin delivery. CsA-LVs allowed the effective incorporation of CsA in the hydrophilic DMAP matrix despite the hydrophobicity of the drug. Polymeric matrix composed of poly (vinyl alcohol) (5% w/v), poly (vinyl pyrrolidine) (15% w/v) and CsA-LV dispersion (10% v/v) led to the formation of CsA-LVs@DMAPs with adequate mechanical properties to penetrate the stratum corneum barrier. The safety and biocompatibility were ensured in an in vitro viability test using HaCaT keratinocytes and L929 fibroblast cell lines. Ex vivo permeability studies in a Franz-diffusion cell setup showed effective drug retention in the skin structure. Finally, CsA-LVs@DMAPs were challenged in an in vivo murine model of delayed-type hypersensitivity to corroborate their potential to ameliorate skin inflammatory conditions. Different findings like photon emission reduction in bioluminescence study, normalisation of histological damage and decrease of inflammatory cytokines point out the effectivity of CsA-LVs@DMAPs to treat these conditions. Overall, our study demonstrates that CsA-LVs@DMAPs can downregulate the skin inflammatory environment which paves the way for their clinical translation and their use as an alternative to corticosteroid-based therapies.
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Affiliation(s)
- Miquel Martínez-Navarrete
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Ave. Vicent Andrés Estellés s/n, 46100, Burjassot, Valencia, Spain
| | - Antonio José Guillot
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Ave. Vicent Andrés Estellés s/n, 46100, Burjassot, Valencia, Spain.
- Department of Biomaterials and Biomedical Technology, University Medical Center Groningen, University of Groningen, Ant. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
| | - Maria C Lobita
- Department of Biomaterials and Biomedical Technology, University Medical Center Groningen, University of Groningen, Ant. Deusinglaan 1, 9713 AV, Groningen, The Netherlands
| | - María Carmen Recio
- Department of Pharmacology, University of Valencia, Ave. Vicent Andrés Estellés s/n, 46100, Burjassot, Valencia, Spain
| | - Rosa Giner
- Department of Pharmacology, University of Valencia, Ave. Vicent Andrés Estellés s/n, 46100, Burjassot, Valencia, Spain
| | - Juan Aparicio-Blanco
- Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain
| | - María Carmen Montesinos
- Department of Pharmacology, University of Valencia, Ave. Vicent Andrés Estellés s/n, 46100, Burjassot, Valencia, Spain
- Interuniversity Research Institute for Molecular Recognition and Technological Development (IDM), University of Valencia, Polytechnic University of Valencia, Valencia, Spain
| | - Hélder A Santos
- Department of Biomaterials and Biomedical Technology, University Medical Center Groningen, University of Groningen, Ant. Deusinglaan 1, 9713 AV, Groningen, The Netherlands
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014, Helsinki, Finland
| | - Ana Melero
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Ave. Vicent Andrés Estellés s/n, 46100, Burjassot, Valencia, Spain
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8
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Malešević A, Tucović D, Kulaš J, Mirkov I, Popović D, Čakić Milošević M, Popov Aleksandrov A. Impact of Skin Exposure to Benzo[a]pyrene in Rat Model: Insights into Epidermal Cell Function and Draining Lymph Node Cell Response. Int J Mol Sci 2024; 25:8631. [PMID: 39201318 PMCID: PMC11354278 DOI: 10.3390/ijms25168631] [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: 07/17/2024] [Revised: 07/29/2024] [Accepted: 08/02/2024] [Indexed: 09/02/2024] Open
Abstract
The skin is a direct target of the air pollutant benzo[a]pyrene (BaP). While its carcinogenic qualities are well-studied, the immunotoxicity of BaP after dermal exposure is less understood. This study examines the immunomodulatory effects of a 10-day epicutaneous BaP application, in environmentally/occupationally relevant doses, by analyzing ex vivo skin immune response (skin explant, epidermal cells and draining lymph node/DLN cell activity), alongside the skin's reaction to sensitization with experimental hapten dinitrochlorobenzene (DNCB). The results show that BaP application disrupts the structure of the epidermal layer and promotes immune cell infiltration in the dermis. BaP exposure led to oxidative stress in epidermal cells, characterized by decreased reduced glutathione and increased AHR and Cyp1A1 expression. Production and gene expression of proinflammatory cytokines (TNF, IL-1β) by epidermal cells decreased, while IL-10 response increased. Decreased spontaneous production of IFN-γ and IL-17, along with unchanged IL-10, was observed in DLC cells, whereas ConA-stimulated production of these cytokines was elevated. Local immunosuppression caused by BaP application seems to reduce the skin's response to an additional stimulus, evidenced by decreased effector activity of DLN cells three days after sensitization with DNCB. These findings provide new insight into the immunomodulatory effects and health risks associated with skin exposure to BaP.
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Affiliation(s)
- Anastasija Malešević
- Immunotoxicology Group, Department of Ecology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, 142 Bulevar Despota Stefana, 11000 Belgrade, Serbia; (A.M.); (D.T.); (J.K.); (I.M.); (D.P.)
| | - Dina Tucović
- Immunotoxicology Group, Department of Ecology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, 142 Bulevar Despota Stefana, 11000 Belgrade, Serbia; (A.M.); (D.T.); (J.K.); (I.M.); (D.P.)
| | - Jelena Kulaš
- Immunotoxicology Group, Department of Ecology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, 142 Bulevar Despota Stefana, 11000 Belgrade, Serbia; (A.M.); (D.T.); (J.K.); (I.M.); (D.P.)
| | - Ivana Mirkov
- Immunotoxicology Group, Department of Ecology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, 142 Bulevar Despota Stefana, 11000 Belgrade, Serbia; (A.M.); (D.T.); (J.K.); (I.M.); (D.P.)
| | - Dušanka Popović
- Immunotoxicology Group, Department of Ecology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, 142 Bulevar Despota Stefana, 11000 Belgrade, Serbia; (A.M.); (D.T.); (J.K.); (I.M.); (D.P.)
| | - Maja Čakić Milošević
- Institute of Zoology, Faculty of Biology, University of Belgrade, 16 Studentski trg, 11000 Belgrade, Serbia;
| | - Aleksandra Popov Aleksandrov
- Immunotoxicology Group, Department of Ecology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, 142 Bulevar Despota Stefana, 11000 Belgrade, Serbia; (A.M.); (D.T.); (J.K.); (I.M.); (D.P.)
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9
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Monedeiro F, Ehall B, Tiffner K, Eberl A, Svehlikova E, Prietl B, Pfeifer V, Senekowitsch J, Remm A, Rebane A, Magnes C, Pieber T, Sinner F, Birngruber T. Characterization of Inflammatory Mediators and Metabolome in Interstitial Fluid Collected with Dermal Open Flow Microperfusion before and at the End of Dupilumab Treatment in Atopic Dermatitis. J Proteome Res 2024; 23:3496-3514. [PMID: 38986055 PMCID: PMC11304394 DOI: 10.1021/acs.jproteome.4c00153] [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: 02/29/2024] [Revised: 06/07/2024] [Accepted: 06/20/2024] [Indexed: 07/12/2024]
Abstract
Dupilumab is a monoclonal antibody approved for the treatment of atopic dermatitis (AD); however, its effects on molecular, cellular, and immunological levels remain to be elucidated. In this study, blood and dermal interstitial fluid (ISF) from nonlesional (NL) and lesional (L) skin were collected from eight patients with moderate to severe AD, before (visit 2-v2) and at the end of a 16-week treatment with dupilumab (visit 10-v10). Clinical treatment effect was demonstrated by significantly decreased AD severity scores at the end of treatment. At v10 versus v2, the percentages of CD4+ interleukin-producing cells showed a decreasing trend in ISF L and NL, unbound IL-4 levels in plasma were increased, IL-5 levels in ISF L reduced, and levels of factors involved in anti-inflammatory pathways and re-epithelization increased. At v2, ISF L showed that AD lesions might have altered amino acid pathways and lipid signaling compared to ISF NL. At v10, ISF L exhibited raised levels of long- and very-long-chain fatty acids and lipids compared to v2. Furthermore, dupilumab administration caused reduced expression of miR-155-5p and miR-378a-3p in ISF L. In conclusion, results from the present study provided novel knowledge by linking local immune and metabolic alterations to AD pathogenesis and treatment response.
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Affiliation(s)
- Fernanda Monedeiro
- HEALTH
− Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz 8010, Austria
| | - Barbara Ehall
- Division
of Endocrinology and Diabetology, Medical
University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria
- BioTechMed, Mozartgasse
12, Graz 8010, Austria
| | - Katrin Tiffner
- HEALTH
− Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz 8010, Austria
| | - Anita Eberl
- HEALTH
− Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz 8010, Austria
| | - Eva Svehlikova
- Division
of Endocrinology and Diabetology, Medical
University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria
| | - Barbara Prietl
- Division
of Endocrinology and Diabetology, Medical
University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria
- Center
for Biomarker Research in Medicine (CBmed) GmbH, Stiftingtalstrasse 5, Graz 8010, Austria
| | - Verena Pfeifer
- Division
of Endocrinology and Diabetology, Medical
University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria
- Center
for Biomarker Research in Medicine (CBmed) GmbH, Stiftingtalstrasse 5, Graz 8010, Austria
| | - Julia Senekowitsch
- Division
of Endocrinology and Diabetology, Medical
University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria
| | - Anu Remm
- Institute
of Biomedicine and Translational Medicine, University of Tartu, Biomeedikum, Ravila 19, Tartu 50411, Estonia
| | - Ana Rebane
- Institute
of Biomedicine and Translational Medicine, University of Tartu, Biomeedikum, Ravila 19, Tartu 50411, Estonia
| | - Christoph Magnes
- HEALTH
− Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz 8010, Austria
| | - Thomas Pieber
- HEALTH
− Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz 8010, Austria
- Division
of Endocrinology and Diabetology, Medical
University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria
- Center
for Biomarker Research in Medicine (CBmed) GmbH, Stiftingtalstrasse 5, Graz 8010, Austria
| | - Frank Sinner
- HEALTH
− Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz 8010, Austria
- Division
of Endocrinology and Diabetology, Medical
University of Graz, Neue Stiftingtalstraße 6, Graz 8010, Austria
| | - Thomas Birngruber
- HEALTH
− Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz 8010, Austria
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10
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Li H, Zhao J, Cao L, Luo Q, Zhang C, Zhang L. The NLRP3 inflammasome in burns: a novel potential therapeutic target. BURNS & TRAUMA 2024; 12:tkae020. [PMID: 38957662 PMCID: PMC11218784 DOI: 10.1093/burnst/tkae020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 04/14/2024] [Accepted: 04/17/2024] [Indexed: 07/04/2024]
Abstract
Burns are an underestimated serious injury negatively impacting survivors physically, psychologically and economically, and thus are a considerable public health burden. Despite significant advancements in burn treatment, many burns still do not heal or develop serious complications/sequelae. The nucleotide-binding oligomerization domain-like receptors (NLRs) family pyrin domain-containing 3 (NLRP3) inflammasome is a critical regulator of wound healing, including burn wound healing. A better understanding of the pathophysiological mechanism underlying the healing of burn wounds may help find optimal therapeutic targets to promote the healing of burn wounds, reduce complications/sequelae following burn, and maximize the restoration of structure and function of burn skin. This review aimed to summarize current understanding of the roles and regulatory mechanisms of the NLRP3 inflammasome in burn wound healing, as well as the preclinical studies of the involvement of NLRP3 inhibitors in burn treatment, highlighting the potential application of NLRP3-targeted therapy in burn wounds.
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Affiliation(s)
- Haihong Li
- Department of Burns and Plastic Surgery, Seventh Affiliated Hospital, Sun Yat-sen University, 628 Zhenyuan Road, Guangming District, Shenzhen 518107, Guangdong Province, China
| | - Junhong Zhao
- Laboratory of Wound Repair and Dermatologic Surgery, Taihe Hospital, Hubei University of Medicine, 32 South Renmin Road, Shiyan 442000, Hubei Province, China
| | - Leilei Cao
- Department of Burns and Plastic Surgery, Seventh Affiliated Hospital, Sun Yat-sen University, 628 Zhenyuan Road, Guangming District, Shenzhen 518107, Guangdong Province, China
| | - Qizhi Luo
- Department of Burns and Plastic Surgery, Seventh Affiliated Hospital, Sun Yat-sen University, 628 Zhenyuan Road, Guangming District, Shenzhen 518107, Guangdong Province, China
| | - Cuiping Zhang
- Research Center for Tissue Repair and Regeneration affiliated to the Medical Innovation Research Department and Fourth Medical Center of PLA General Hospital, 51 Fucheng Road, Beijing 100048, China
| | - Lei Zhang
- Department of Psychiatry and Clinical Psychology, Seventh Affiliated Hospital, Sun Yat-sen University, 628 Zhenyuan Road, Guangming District, Shenzhen 518107, Guangdong Province, China
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11
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Wennervaldt M, Vaher H, Ahlström MG, Bischofberger N, Menné T, Thyssen JP, Johansen JD, Bonefeld CM. Subclinical immune responses to nickel in sensitized individuals-a dose-response study. Contact Dermatitis 2024; 91:1-10. [PMID: 38577784 DOI: 10.1111/cod.14549] [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: 11/17/2023] [Revised: 02/10/2024] [Accepted: 03/08/2024] [Indexed: 04/06/2024]
Abstract
BACKGROUND Nickel is the leading cause of contact allergy in Europe, with 14.5% of the adult population being sensitized. Despite regulations limiting nickel release from consumer items, the incidence and prevalence of nickel allergy remain high. OBJECTIVE To investigate the clinical and subclinical immune response to low-dose nickel exposure on nickel pre-exposed skin to assess the adequacy of current regulatory limits. METHOD Nickel-allergic and healthy controls were patch tested with nickel twice with a 3-4 weeks interval. The first exposure used the diagnostic concentration of 2000 μg/cm2 nickel sulphate, and the same skin areas were then re-exposed to 0.2, 0.5, 12.8 and 370 μg/cm2 nickel sulphate. After 48 h, the patch reactions were examined for clinical signs of eczema, and skin biopsies were collected. The transcriptomic immune profile was analysed with Nanostring nCounter and quantitative polymerase chain reaction. RESULTS Two nickel-allergic participants (15%) had clinical reactions to the regulatory limiting doses for nickel (0.2/0.5 μg/cm2) following re-exposure. There was immune activation in all skin areas following re-exposure to nickel, predominantly mediated by up-regulation of cytokines and chemokines. In all nickel re-exposed skin areas, 81 genes were up-regulated independent from the clinical response. In skin areas exposed to 0.2 μg/cm2, 101 immune-related genes were differentially expressed, even when no clinical response was observed. Healthy controls showed up-regulation of three genes in response to nickel re-exposures without any clinical reactions. CONCLUSION Immune activation can be induced in skin with local memory to nickel upon challenge with nickel doses within the regulatory limits. Our findings suggest that the regulatory limits in the European nickel regulation may not provide sufficient protection for consumers against low-dose exposures.
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Affiliation(s)
- Michael Wennervaldt
- Department of Dermatology and Allergy, National Allergy Research Centre, Copenhagen University Hospital Herlev-Gentofte, Hellerup, Denmark
| | - Helen Vaher
- Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark
| | - Malin G Ahlström
- Department of Dermatology and Allergy, National Allergy Research Centre, Copenhagen University Hospital Herlev-Gentofte, Hellerup, Denmark
| | - Nuno Bischofberger
- Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark
| | - Torkil Menné
- Department of Dermatology and Allergy, National Allergy Research Centre, Copenhagen University Hospital Herlev-Gentofte, Hellerup, Denmark
| | - Jacob P Thyssen
- Department of Dermatology and Allergy, National Allergy Research Centre, Copenhagen University Hospital Herlev-Gentofte, Hellerup, Denmark
| | - Jeanne D Johansen
- Department of Dermatology and Allergy, National Allergy Research Centre, Copenhagen University Hospital Herlev-Gentofte, Hellerup, Denmark
| | - Charlotte M Bonefeld
- Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark
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12
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Yang Y, Pan Y, Liu B, Zhang Y, Yin C, Wang J, Nie H, Xu R, Tai Y, He X, Shao X, Liang Y, Fang J, Liu B. Neutrophil-derived oxidative stress contributes to skin inflammation and scratching in a mouse model of allergic contact dermatitis via triggering pro-inflammatory cytokine and pruritogen production in skin. Biochem Pharmacol 2024; 223:116163. [PMID: 38522555 DOI: 10.1016/j.bcp.2024.116163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 03/11/2024] [Accepted: 03/21/2024] [Indexed: 03/26/2024]
Abstract
Allergic contact dermatitis (ACD) is a common skin disease featured with skin inflammation and a mixed itch/pain sensation. The itch/pain causes the desire to scratch, affecting both physical and psychological aspects of patients. Nevertheless, the mechanisms underlying itch/pain sensation of ACD still remain elusive. Here, we found that oxidative stress and oxidation-related injury were remarkably increased in the inflamed skin of a mouse model of ACD. Reducing oxidative stress significantly attenuated itch/pain-related scratching, allokonesis and skin inflammation. RNA-Sequencing reveals oxidative stress contributes to a series of skin biological processes, including inflammation and immune response. Attenuating oxidative stress reduces overproduction of IL-1β and IL-33, two critical cytokines involved in inflammation and pain/itch, in the inflamed skin of model mice. Exogenously injecting H2O2 into the neck skin of naïve mice triggered IL-33 overproduction in skin keratinocytes and induced scratching, which was reduced in mice deficient in IL-33 receptor ST2. ACD model mice showed remarkable neutrophil infiltration in the inflamed skin. Blocking neutrophil infiltration reduced oxidative stress and attenuated scratching and skin inflammation. Therefore, our study reveals a critical contribution of neutrophil-derived oxidative stress to skin inflammation and itch/pain-related scratching of ACD model mice via mechanisms involving the triggering of IL-33 overproduction in skin keratinocytes. Targeting skin oxidative stress may represent an effective therapy for ameliorating ACD.
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Affiliation(s)
- Yunqin Yang
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yushuang Pan
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China
| | - Boyu Liu
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yunwen Zhang
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China
| | - Chengyu Yin
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jie Wang
- Department of Rehabilitation in Traditional Chinese Medicine, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Huimin Nie
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ruoyao Xu
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yan Tai
- Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiaofen He
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiaomei Shao
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yi Liang
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jianqiao Fang
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China
| | - Boyi Liu
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China.
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13
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Kleuskens MTA, Haasnoot ML, Garssen J, Bredenoord AJ, van Esch BCAM, Redegeld FA. Transcriptomic profiling of the acute mucosal response to local food injections in adults with eosinophilic esophagitis. J Allergy Clin Immunol 2024; 153:780-792. [PMID: 37972740 DOI: 10.1016/j.jaci.2023.10.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 10/12/2023] [Accepted: 10/27/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND Exposure of the esophageal mucosa to food allergens can cause acute mucosal responses in patients with eosinophilic esophagitis (EoE), but the underlying local immune mechanisms driving these acute responses are not well understood. OBJECTIVE We sought to gain insight into the early transcriptomic changes that occur during an acute mucosal response to food allergens in EoE. METHODS Bulk RNA sequencing was performed on esophageal biopsy specimens from adult patients with EoE (n = 5) collected before and 20 minutes after intramucosal injection of various food extracts in the esophagus. Baseline biopsy specimens from control subjects without EoE (n = 5) were also included. RESULTS At baseline, the transcriptome of the patients with EoE showed increased expression of genes related to an EoE signature. After local food injection, we identified 40 genes with a potential role in the early immune response to food allergens (most notably CEBPB, IL1B, TNFSF18, PHLDA2, and SLC15A3). These 40 genes were enriched in processes related to immune activation, such as the acute-phase response, cellular responses to external stimuli, and cell population proliferation. TNFSF18 (also called GITRL), a member of the TNF superfamily that is best studied for its costimulatory effect on T cells, was the most dysregulated early EoE gene, showing a 12-fold increase compared with baseline and an 18-fold increase compared with a negative visual response. Further experiments showed that the esophageal epithelium may be an important source of TNFSF18 in EoE, which was rapidly induced by costimulating esophageal epithelial cells with the EoE-relevant cytokines IL-13 and TNF-α. CONCLUSIONS Our data provide unprecedented insight into the transcriptomic changes that mediate the acute mucosal immune response to food allergens in EoE and suggest that TNFSF18 may be an important effector molecule in this response.
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Affiliation(s)
- Mirelle T A Kleuskens
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Maria L Haasnoot
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands; Danone Nutricia Research, Utrecht, The Netherlands
| | - Albert J Bredenoord
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands
| | - Betty C A M van Esch
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands; Danone Nutricia Research, Utrecht, The Netherlands.
| | - Frank A Redegeld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
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14
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Xiao Y, Han M, Chen Y, Li YZ, Zhang YY, Chen L, Huang S, Zhou XL. In vitro and in vivo biological evaluation of Lappaconitine derivatives as potential anti-inflammatory agents. Chem Biodivers 2024; 21:e202301761. [PMID: 38117633 DOI: 10.1002/cbdv.202301761] [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: 11/07/2023] [Revised: 12/12/2023] [Accepted: 12/18/2023] [Indexed: 12/22/2023]
Abstract
Natural products and their derivatives are a precious treasure in the pursuit of potent anti-inflammatory drugs. In this work, we measured the toxicity of 78 LA derivatives at 20 μM using MTT, then we evaluated the NO release of compounds without obvious toxicity in LPS-induced RAW.264.7 by Griess reagent, we identified three compounds, namely compounds 6, 19, 70, which exhibited promising anti-inflammatory potential. These compounds exhibited IC50 values of 10.34±2.05 μM, 18.18±4.80 μM and 15.66±0.88 μM. In addition, through ELISA kits, compounds 6, 19, 70 significantly reduce the production of inflammatory factors (TNF-α, IL-6, IL-1β). Real-time PCR and western blot analysis showed that compounds 6, 19, 70 inhibited the mRNA and protein expression of iNOS and COX-2. Notably, compound 6 exhibited the most potent inhibitory activity. In vitro, it inhibits LPS-induced phosphorylation of NF-κB p65, IκBα, ERK1/2, JNK, and p38 MAPKs in RAW264.7 cells. In vivo, compound 6 potently inhibits the secretion of inflammatory mediators and neutrophil activation in ALI mice. Our findings suggest that compound 6 may be a potential anti-inflammatory drug.
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Affiliation(s)
- Yan Xiao
- School of Life Science and Engineering, Southwest Jiaotong University, 610031, Chengdu, Sichuan, People's Republic of China
| | - Meng Han
- School of Life Science and Engineering, Southwest Jiaotong University, 610031, Chengdu, Sichuan, People's Republic of China
| | - Ying Chen
- Sichuan Provincial Administration of Traditional Chinese Medicine, 610017, Chengdu, Sichuan, People's Republic of China
| | - Yu-Zhu Li
- School of Life Science and Engineering, Southwest Jiaotong University, 610031, Chengdu, Sichuan, People's Republic of China
| | - Yin-Yong Zhang
- School of Life Science and Engineering, Southwest Jiaotong University, 610031, Chengdu, Sichuan, People's Republic of China
| | - Lin Chen
- School of Life Science and Engineering, Southwest Jiaotong University, 610031, Chengdu, Sichuan, People's Republic of China
| | - Shuai Huang
- School of Life Science and Engineering, Southwest Jiaotong University, 610031, Chengdu, Sichuan, People's Republic of China
| | - Xian-Li Zhou
- School of Life Science and Engineering, Southwest Jiaotong University, 610031, Chengdu, Sichuan, People's Republic of China
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15
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Mraz V, Lohmann RKD, Menzel M, Hawkes A, Vaher H, Funch AB, Jee MH, Gadsbøll ASØ, Weber JF, Yeung K, Ødum N, Woetmann A, McKay D, Witherden D, Geisler C, Bonefeld CM. The junctional adhesion molecule-like protein (JAML) is important for the inflammatory response during contact hypersensitivity. Contact Dermatitis 2023; 89:323-334. [PMID: 37619972 PMCID: PMC11034946 DOI: 10.1111/cod.14409] [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: 06/14/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 08/26/2023]
Abstract
BACKGROUND The junctional adhesion molecule-like protein (JAML) plays important roles in wound healing and activation of epidermal γδ T cells in mice. Whether JAML plays a role in contact hypersensitivity (CHS), the animal model of allergic contact dermatitis (ACD), is not known. METHODS To examine the role of JAML in CHS, we used various mouse models of CHS in JAML knockout (KO) and wild-type (WT) mice. Furthermore, the expression of the JAML ligand coxsackievirus and adenovirus receptor (CXADR) on keratinocytes was accessed in vitro and in vivo. RESULTS JAML KO mice had a diminished inflammatory response during both the sensitization and elicitation phase of CHS and had reduced numbers of CD8+ and CD4+ T cells in the epidermis. Furthermore, interferon γ (IFNγ), interleukin 1β (IL-1β) and CXCL10 production were significantly reduced in JAML KO mice during the elicitation phase. We found that CD8+ T cells express JAML and that JAML is essential for rapid flare-up responses to contact allergens. Finally, we show that keratinocytes up-regulate the JAML ligand CXADR following exposure to contact allergens. CONCLUSION Our study is the first to show a central role of JAML in CHS and reveals a potential new target for the treatment of ACD in humans.
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Affiliation(s)
- Veronika Mraz
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Rebecca K. D. Lohmann
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Mandy Menzel
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
- Respiratory Research Unit, Department of Respiratory Medicine, Bispebjerg Hospital, Copenhagen, Denmark
| | - Alana Hawkes
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Helen Vaher
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Anders B. Funch
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
- Department of Dermatology and Allergy, National Allergy Research Center, Copenhagen University Hospital Gentofte, Hellerup, Denmark
| | - Mia H. Jee
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Anne-Sofie Ø. Gadsbøll
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Julie F. Weber
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Kelvin Yeung
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
- Department of Dermatology and Allergy, National Allergy Research Center, Copenhagen University Hospital Gentofte, Hellerup, Denmark
| | - Niels Ødum
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Anders Woetmann
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Dianne McKay
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Deborah Witherden
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Carsten Geisler
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
| | - Charlotte M. Bonefeld
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark
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16
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Höper T, Karkossa I, Dumit VI, von Bergen M, Schubert K, Haase A. A comparative proteomics analysis of four contact allergens in THP-1 cells shows distinct alterations in key metabolic pathways. Toxicol Appl Pharmacol 2023; 475:116650. [PMID: 37541627 DOI: 10.1016/j.taap.2023.116650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/21/2023] [Accepted: 07/31/2023] [Indexed: 08/06/2023]
Abstract
Allergic contact dermatitis (ACD) is the predominant form of immunotoxicity in humans. The sensitizing potential of chemicals can be assessed in vitro. However, a better mechanistic understanding could improve the current OECD-validated test battery. The aim of this study was to get insights into toxicity mechanisms of four contact allergens, p-benzoquinone (BQ), 2,4-dinitrochlorobenzene (DNCB), p-nitrobenzyl bromide (NBB) and NiSO4, by analyzing differential proteome alterations in THP-1 cells using two common proteomics workflows, stable isotope labeling by amino acids in cell culture (SILAC) and label-free quantification (LFQ). Here, SILAC was found to deliver more robust results. Overall, the four allergens induced similar responses in THP-1 cells, which underwent profound metabolic reprogramming, including a striking upregulation of the TCA cycle accompanied by pronounced induction of the Nrf2 oxidative stress response pathway. The magnitude of induction varied between the allergens with DNCB and NBB being most potent. A considerable overlap between transcriptome-based signatures of the GARD assay and the proteins identified in our study was found. When comparing the results of this study to a previous proteomics study in human primary monocyte-derived dendritic cells, we found a rather low share in regulated proteins. However, on pathway level, the overlap was high, indicating that affected pathways rather than single proteins are more eligible to investigate proteomic changes induced by contact allergens. Overall, this study confirms the potential of proteomics to obtain a profound mechanistic understanding, which may help improving existing in vitro assays for skin sensitization.
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Affiliation(s)
- Tessa Höper
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany; Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universität Berlin, Berlin, Germany
| | - Isabel Karkossa
- Department of Molecular Systems Biology, UFZ, Helmholtz-Centre for Environmental Research, Leipzig, Germany
| | - Verónica I Dumit
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany
| | - Martin von Bergen
- Department of Molecular Systems Biology, UFZ, Helmholtz-Centre for Environmental Research, Leipzig, Germany; Institute of Biochemistry, Leipzig University, Leipzig, Germany; German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany
| | - Kristin Schubert
- Department of Molecular Systems Biology, UFZ, Helmholtz-Centre for Environmental Research, Leipzig, Germany
| | - Andrea Haase
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany.
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17
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Bai Z, Hu H, Hu F, Ji J, Ji Z. Bone marrow mesenchymal stem cellsderived exosomes stabilize atherosclerosis through inhibiting pyroptosis. BMC Cardiovasc Disord 2023; 23:441. [PMID: 37679676 PMCID: PMC10486039 DOI: 10.1186/s12872-023-03453-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 08/16/2023] [Indexed: 09/09/2023] Open
Abstract
OBJECTIVES This study aimed to determine the effects of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (BMSC-EXO) on atherosclerosis (AS), and its related underlying mechanisms. METHODS Exosomes were isolated from mouse BMSCs, and identified by transmission electron microscopy (TEM), Nanosight (NTA), and western blot. A mouse AS model was established, and exosomes were injected into the tail vein. Total cholesterol (TC) and triglycerides (TG) were detected using their corresponding assay kits. The contents of IL-1β and IL-18 in serum were detected by ELISA. The mRNA and protein expression levels of GSDMD, Caspase1, and NLRP3 were detected by qRT-PCR and Western blot. Finally, aortic tissues in the Model and BMSC-EXO groups were sent for sequencing. RESULTS TEM, NTA, and western blot indicated successful isolation of exosomes. Compared with the control group, the TC, TG contents, IL-1β and IL-18 concentrations of the mice in the Model group were significantly increased; nonetheless, were significantly lower after injected with BMSC-EXO than those in the Model group (p < 0.05). Compared with the control group, the expressions of NLRP3, caspase-1 and GSDMD were significantly up-regulated in the Model group (p < 0.05), while the expressions of NLRP3, caspase-1, and GSDMD were significantly down-regulated by BMSC-EXO. By sequencing, a total of 3852 DEGs were identified between the Model and BMSC-EXO group and were significantly enriched in various biological processes and pathways related to mitochondrial function, metabolism, inflammation, and immune response. CONCLUSION AS can induce pyroptosis, and BMSC-EXO can reduce inflammation and alleviate the progression of AS by inhibiting NLRP3/Caspase-1/GSDMD in the pyroptosis pathway.
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Affiliation(s)
- Zhibin Bai
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Medical School, Zhongda Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, Jiangsu, China
| | - Haolin Hu
- Department of General Surgery, Institute for Minimally Invasive Surgery, Medical School, ZhongDa Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, Jiangsu, China
| | - Fangfang Hu
- Department of General Surgery, Institute for Minimally Invasive Surgery, Medical School, ZhongDa Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, Jiangsu, China
| | - Jiajie Ji
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Medical School, Zhongda Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, Jiangsu, China
| | - Zhenling Ji
- Department of General Surgery, Institute for Minimally Invasive Surgery, Medical School, ZhongDa Hospital, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, Jiangsu, China.
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18
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Wu L, Liu D, Fang X, Zhang Y, Guo N, Lu F, Kwak-Kim J, Wang Y. Increased serum IL-12 levels are associated with adverse IVF outcomes. J Reprod Immunol 2023; 159:103990. [PMID: 37451158 DOI: 10.1016/j.jri.2023.103990] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/20/2023] [Accepted: 07/10/2023] [Indexed: 07/18/2023]
Abstract
Interleukin-12 (IL-12) is involved in the occurrence and development of many diseases, such as preeclampsia, intrauterine growth restriction, preterm labor, and recurrent pregnancy losses. This study aimed to determine whether a high serum level of IL-12 was associated with adverse in vitro fertilization (IVF) outcomes. Included infertile women with high serum IL-12 levels who underwent IVF cycles and infertile controls with pure tubal etiology. The impact of serum IL-12 on baseline and clinical characteristics, immune-related indicators, IVF laboratory, and pregnancy outcomes were compared. In addition, the correlation of follicular fluid IL-12 and serum IL-12 level and the role of IL-12 in apoptosis of granulosa cells (GCs) was investigated. Women with high serum IL-12 levels had lower numbers of retrieved oocytes, embryos, perfect and available embryos, lower rates of perfect and available embryos, and blastocyst formation. Additionally, significantly higher levels of serum Th1, Th2, and Th17-related cytokines were observed in women with high serum IL-12 levels than in the controls. Meanwhile, the follicular fluid IL-12 levels were positively correlated with serum IL-12 levels, and IL-12 promoted apoptosis of GCs in vitro. We concluded that women with serum high IL-12 levels may have adverse IVF outcomes, partly by promoting apoptosis of GCs. Therefore, early screening for cytokines, especially IL-12, and appropriate consultation for couples receiving IVF-ET should be considered. In addition, specific immune and inflammatory mechanisms associated with high serum IL-12 levels should be further explored.
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Affiliation(s)
- Li Wu
- Reproductive and Genetic Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Dongyan Liu
- Reproductive and Genetic Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Xuhui Fang
- Reproductive and Genetic Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Yu Zhang
- Reproductive and Genetic Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Nan Guo
- Reproductive and Genetic Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Fangting Lu
- Reproductive and Genetic Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Joanne Kwak-Kim
- Reproductive Medicine and Immunology, Obstetrics and Gynecology, Clinical Sciences Department, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Vernon Hills, IL 60061, USA; Center for Cancer Cell Biology, Immunology and Infection Diseases, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
| | - Yanshi Wang
- Reproductive and Genetic Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
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19
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Basketter DA. Risk management of skin sensitisers: A commentary. Regul Toxicol Pharmacol 2023; 140:105384. [PMID: 37028500 DOI: 10.1016/j.yrtph.2023.105384] [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: 01/16/2023] [Revised: 03/10/2023] [Accepted: 03/25/2023] [Indexed: 04/09/2023]
Abstract
Historically, allergic contact dermatitis (ACD) to chemicals encouraged hazard identification improvements, more sophisticated risk assessment and implementation of regulatory strategies, including banning of specific sensitising substances. The validation process applied to hazard identification methods demonstrates their accuracy; their use to characterise sensitiser potency facilitates quantitative and transparent risk assessment. Diagnostic patch testing at dermatology clinics worldwide delivers feedback showing where risk assessment/management has been insufficient or did not target the exposure of concern, thereby facilitating improvements. When urgent action to protect human health was required, regulations limited/banned, specific skin sensitisers. This can be seen in practice with the fragrance industry, a known source of ACD, thus requiring risk management, usually restrictions to limit allergy induction, and very rarely specific bans on ingredients. Experience and development of more sophisticated tools, e.g. to assess aggregate exposure from multitude of consumer product types, has led to repeated adaptation of risk assessment and promulgation of updated fragrance use limits. Although targeted control may not always lead to rapid change in the overall clinical picture, it is preferable to a blanket undifferentiated regulatory control of all sensitisers, resulting in unwarranted restrictions for many uses of no health concern, with consequent substantial socio-economic impacts.
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20
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Characterization of Metal-Specific T-Cells in Inflamed Oral Mucosa in a Novel Murine Model of Chromium-Induced Allergic Contact Dermatitis. Int J Mol Sci 2023; 24:ijms24032807. [PMID: 36769119 PMCID: PMC9917800 DOI: 10.3390/ijms24032807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/23/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
The element chromium (Cr) is a component of several types of alloys found in the environment, or utilized in dentistry, that may cause intraoral metal contact allergy. However, the pathological mechanism of intraoral Cr allergy remains unclear because there is no established animal model of Cr allergy in the oral mucosa. In this study, we established a novel murine model of Cr-induced intraoral metal contact allergy and elucidated the immune response in terms of cytokine profiles and T-cell receptor repertoire. Two sensitizations with Cr plus lipopolysaccharide solution into the postauricular skin were followed by a single Cr challenge of the oral mucosa to generate the intraoral metal contact allergy model. Histological examination revealed that CD3+ T-cells had infiltrated the allergic oral mucosa one day after exposure to the allergen. The increase in T-cell markers and cytokines in allergic oral mucosa was also confirmed via quantitative PCR analysis. We detected Cr-specific T-cells bearing TRAV12D-1-TRAJ22 and natural killer (NK) T-cells in the oral mucosa and lymph nodes. Our model demonstrated that Cr-specific T-cells and potent NKT-cell activation may be involved in the immune responses of Cr-induced intraoral metal contact allergy.
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21
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Tang H, Huang L, Hu J. Inhibition of the m6A Methyltransferase METTL3 Attenuates the Inflammatory Response in Fusarium solani-Induced Keratitis via the NF-κB Signaling Pathway. Invest Ophthalmol Vis Sci 2022; 63:2. [PMID: 36194423 PMCID: PMC9547362 DOI: 10.1167/iovs.63.11.2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose The purpose of this study was to elucidate the effect of methyltransferase-like enzyme 3 (METTL3) on inflammation and the NF-κB signaling pathway in fungal keratitis (FK). Methods We established corneal stromal cell models and FK mouse models by incubation with Fusarium solani. The overall RNA N6-methyladenosine (m6A) level was determined using an m6A RNA methylation assay kit. The expression of METTL3 was quantified via real-time quantitative polymerase chain reaction (RT–PCR), Western blotting, and immunofluorescence. Subsequently, the level of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) was identified by Western blotting and immunofluorescence. Moreover, we assessed the effect of METTL3 by transfecting cells with siRNA (in vitro) or adeno-associated virus (in vivo). Hematoxylin and eosin (H&E) staining and slit-lamp biomicroscopy were performed to evaluate corneal damage. Furthermore, the state of NF-κB signaling pathway activation was examined by Western blotting. In addition, RT–PCR and enzyme-linked immunosorbent assays (ELISAs) were performed to evaluate levels of the pro-inflammatory factors interleukin-1β (IL-1β), interleukin-6 (IL-6) and TNF-ɑ. Results Our data demonstrated that the levels of the RNA m6A methylation and METTL3 were dramatically increased and that the NF-κB signaling pathway was activated in Fusarium solani-induced keratitis. Inhibition of METTL3 decreased the level of TRAF6, downregulated the phospho-p65(p-p65)/p65 and phospho-IκB(p-IκB)/IκB protein ratios, simultaneously attenuating the inflammatory response and fungal burden in FK. Conclusions Our research suggests that the m6A methyltransferase METTL3 regulates the inflammatory response in FK by modulating the NF-κB signaling pathway.
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Affiliation(s)
- Hanfeng Tang
- Department of Ophthalmology, Fujian Medical University Union Hospital, Fu Zhou, China
| | - Liwei Huang
- Department of Ophthalmology, Fujian Medical University Union Hospital, Fu Zhou, China
| | - Jianzhang Hu
- Department of Ophthalmology, Fujian Medical University Union Hospital, Fu Zhou, China
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22
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Immunological Pathomechanisms of Spongiotic Dermatitis in Skin Lesions of Atopic Dermatitis. Int J Mol Sci 2022; 23:ijms23126682. [PMID: 35743125 PMCID: PMC9223609 DOI: 10.3390/ijms23126682] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 06/10/2022] [Accepted: 06/13/2022] [Indexed: 12/18/2022] Open
Abstract
Atopic dermatitis (AD) is a chronic pruritic skin disease with a complex pathogenesis underlying its heterogeneous clinical phenotypes and endotypes. The skin manifestation of AD reflects the cytokine milieu of a type-2-dominant immunity axis induced by genetic predisposition, innate immunity dysregulation, epidermal barrier defects, and allergic inflammation. However, the detailed pathomechanism of eczematous dermatitis, which is the principal characteristic of AD, remains unclear. This review examines previous studies demonstrating research progress in this area and considers the immunological pathomechanism of “spongiotic dermatitis”, which is the histopathological hallmark of eczematous dermatitis. Studies in this field have revealed the importance of IgE-mediated delayed-type hypersensitivity, the Fas/Fas-ligand system, and cell-mediated cytotoxicity in inducing the apoptosis of keratinocytes in spongiotic dermatitis. Recent studies have demonstrated that, together with infiltrating CD4 T cells, IgE-expressing dendritic cells (i.e., inflammatory dendritic epidermal cells and Langerhans cells) that capture specific allergens (i.e., house dust mites) are present in the spongiotic epidermis of lichenified eczema in patients with IgE-allergic AD. These findings suggest that IgE-mediated delayed-type hypersensitivity plays a pivotal role in the pathogenesis of spongiotic dermatitis in the skin lesions of AD.
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23
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Synthesis and anti-inflammatory activity of paeonol derivatives with etherized aryl urea by regulating TLR4/MyD88 signaling pathway in RAW264.7 cell. Bioorg Chem 2022; 127:105939. [PMID: 35700569 DOI: 10.1016/j.bioorg.2022.105939] [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: 10/05/2021] [Revised: 06/05/2022] [Accepted: 06/06/2022] [Indexed: 11/21/2022]
Abstract
Thirty-three novel paeonol etherized aryl urea derivatives (PEUs) were synthesized via a bromination-Williamson Ether Synthesis-deprotection-nucleophilic addition reaction sequence. The structures of PEUs were characterized by LC-MS, HRMS, 1H NMR and 13C NMR spectra. The levels of nitric oxide (NO), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages were initially employed to evaluate the anti-inflammatory effects of all compounds. Remarkably, b16 exhibited a good anti-inflammatory activity at 2.5 μm which is the same as the potency of paeonol at 20 μm. The results of mechanism research displayed that the anti-inflammatory effect of b16 was ascribed to the inhibition of the TLR4/MyD88 signaling pathway and inflammatory factors. Additionally, b16 distinctly reduced the generation of free radicals in macrophages and strikingly increased the mitochondrial membrane potential. According to the structure-activity relationships (SAR) of PEUs, the incorporation of halogens on the benzene ring and the hydrogen of phenol hydroxyl substituted by aryl urea, were beneficial to enhance the anti-inflammatory activities. Molecular docking results illustrated that the binding ability of b16 to TLR4 was stronger than that of paeonol. In summary, the novel aryl urea-derivied paeonol b16 could be a new promising candidate for the treatment of inflammation-related diseases.
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24
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Goksøyr L, Funch AB, Okholm AK, Theander TG, de Jongh WA, Bonefeld CM, Sander AF. Preclinical Efficacy of a Capsid Virus-like Particle-Based Vaccine Targeting IL-1β for Treatment of Allergic Contact Dermatitis. Vaccines (Basel) 2022; 10:vaccines10050828. [PMID: 35632584 PMCID: PMC9143278 DOI: 10.3390/vaccines10050828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/17/2022] [Accepted: 05/18/2022] [Indexed: 02/05/2023] Open
Abstract
Hypersensitivity to a contact allergen is one of the most abundant forms of inflammatory skin disease. Today, more than 20% of the general population are sensitized to one or more contact allergens, making this disease an important healthcare issue, as re-exposure to the allergen can initiate the clinical disease termed allergic contact dermatitis (ACD). The current standard treatment using corticosteroids is effective, but it has side effects when used for longer periods. Therefore, there is a need for new alternative therapies for severe ACD. In this study, we used the versatile Tag/Catcher AP205 capsid virus-like particle (cVLP) vaccine platform to develop an IL-1β-targeted vaccine and to assess the immunogenicity and in vivo efficacy of the vaccine in a translational mouse model of ACD. We show that vaccination with cVLPs displaying full-length murine IL-1β elicits high titers of neutralizing antibodies, leading to a significant reduction in local IL-1β levels as well as clinical symptoms induced by treatment with 1-Fluoro-2,4-dinitrobenzene (DNFB). Moreover, we show that a single amino acid mutation in muIL-1β reduces the biological activity while maintaining the ability to induce neutralizing antibodies. Collectively, the data suggest that a cVLP-based vaccine displaying full-length IL-1β represents a promising vaccine candidate for use as an alternative treatment modality against severe ACD.
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Affiliation(s)
- Louise Goksøyr
- Centre for Medical Parasitology, Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (L.G.); (A.K.O.); (T.G.T.)
- AdaptVac Aps, 2200 Copenhagen, Denmark;
| | - Anders B. Funch
- LEO Foundation Skin Immunology Research Center, Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (A.B.F.); (C.M.B.)
| | - Anna K. Okholm
- Centre for Medical Parasitology, Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (L.G.); (A.K.O.); (T.G.T.)
| | - Thor G. Theander
- Centre for Medical Parasitology, Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (L.G.); (A.K.O.); (T.G.T.)
| | | | - Charlotte M. Bonefeld
- LEO Foundation Skin Immunology Research Center, Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (A.B.F.); (C.M.B.)
| | - Adam F. Sander
- Centre for Medical Parasitology, Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; (L.G.); (A.K.O.); (T.G.T.)
- AdaptVac Aps, 2200 Copenhagen, Denmark;
- Correspondence:
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25
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Vallion R, Hardonnière K, Bouredji A, Damiens MH, Deloménie C, Pallardy M, Ferret PJ, Kerdine-Römer S. The Inflammatory Response in Human Keratinocytes Exposed to Cinnamaldehyde Is Regulated by Nrf2. Antioxidants (Basel) 2022; 11:antiox11030575. [PMID: 35326225 PMCID: PMC8945052 DOI: 10.3390/antiox11030575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/09/2022] [Accepted: 03/13/2022] [Indexed: 12/24/2022] Open
Abstract
Keratinocytes (KC) play a crucial role in epidermal barrier function, notably through their metabolic activity and the detection of danger signals. Chemical sensitizers are known to activate the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), leading to cellular detoxification and suppressed proinflammatory cytokines such as IL-1β, a key cytokine in skin allergy. We investigated the role of Nrf2 in the control of the proinflammatory response in human KC following treatment with Cinnamaldehyde (CinA), a well-known skin sensitizer. We used the well-described human KC cell line KERTr exposed to CinA. Our results showed that 250 μM of CinA did not induce any Nrf2 accumulation but increased the expression of proinflammatory cytokines. In contrast, 100 μM of CinA induced a rapid accumulation of Nrf2, inhibited IL-1β transcription, and downregulated the zymosan-induced proinflammatory response. Moreover, Nrf2 knockdown KERTr cells (KERTr ko) showed an increase in proinflammatory cytokines. Since the inhibition of Nrf2 has been shown to alter cellular metabolism, we performed metabolomic and seahorse analyses. The results showed a decrease in mitochondrial metabolism following KERTr ko exposure to CinA 100 µM. In conclusion, the fate of Nrf2 controls proinflammatory cytokine production in KCs that could be linked to its capacity to preserve mitochondrial metabolism upon chemical sensitizer exposure.
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Affiliation(s)
- Romain Vallion
- Inserm, Inflammation Microbiome and Immunosurveillance, Université Paris-Saclay, 92290 Châtenay-Malabry, France; (R.V.); (K.H.); (A.B.); (M.-H.D.); (M.P.)
- Safety Assessment Department, Pierre Fabre Dermo Cosmétique, 31000 Toulouse, France;
| | - Kévin Hardonnière
- Inserm, Inflammation Microbiome and Immunosurveillance, Université Paris-Saclay, 92290 Châtenay-Malabry, France; (R.V.); (K.H.); (A.B.); (M.-H.D.); (M.P.)
| | - Abderrahmane Bouredji
- Inserm, Inflammation Microbiome and Immunosurveillance, Université Paris-Saclay, 92290 Châtenay-Malabry, France; (R.V.); (K.H.); (A.B.); (M.-H.D.); (M.P.)
| | - Marie-Hélène Damiens
- Inserm, Inflammation Microbiome and Immunosurveillance, Université Paris-Saclay, 92290 Châtenay-Malabry, France; (R.V.); (K.H.); (A.B.); (M.-H.D.); (M.P.)
| | - Claudine Deloménie
- Inserm US31, CNRS UMS3679, Ingénierie et Plateformes au Service de l’Innovation Thérapeutique, Université Paris-Saclay, 92296 Châtenay-Malabry, France;
| | - Marc Pallardy
- Inserm, Inflammation Microbiome and Immunosurveillance, Université Paris-Saclay, 92290 Châtenay-Malabry, France; (R.V.); (K.H.); (A.B.); (M.-H.D.); (M.P.)
| | - Pierre-Jacques Ferret
- Safety Assessment Department, Pierre Fabre Dermo Cosmétique, 31000 Toulouse, France;
| | - Saadia Kerdine-Römer
- Inserm, Inflammation Microbiome and Immunosurveillance, Université Paris-Saclay, 92290 Châtenay-Malabry, France; (R.V.); (K.H.); (A.B.); (M.-H.D.); (M.P.)
- Correspondence: ; Tel.: +33-(0)-1-46-83-57-79
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