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Salman S, Paulet V, Hardonnière K, Kerdine‐Römer S. The role of NRF2 transcription factor in inflammatory skin diseases. Biofactors 2025; 51:e70013. [PMID: 40207460 PMCID: PMC11983367 DOI: 10.1002/biof.70013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 03/25/2025] [Indexed: 04/11/2025]
Abstract
The skin is the body's largest organ and performs several vital functions, such as controlling the movement of essential substances while protecting against external threats. Although mainly composed of keratinocytes (KCs), the skin also contains a complex network of immune cells that play a critical role in host defense and maintaining skin homeostasis. KCs proliferate in the basal layer of the epidermis and undergo differentiation, altering their functional and phenotypic characteristics. These differentiation steps are crucial for the stratification of the epidermis and the formation of the stratum corneum, ensuring the skin barrier's functions. Exposure to UV, environmental pollutants, or chemicals can lead to an overproduction of reactive species of oxygen (ROS), leading to oxidative stress. To ensure redox homeostasis and prevent damage resulting from the formation of ROS, the skin has an extensive network of antioxidant defense systems, mainly orchestrated by the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. Indeed, Nrf2 induces the expression of detoxification and antioxidant enzymes and suppresses inductions of pro-inflammatory cytokine genes. In this context, Nrf2 is critical in preserving skin functions such as epidermal differentiation, regulating skin immunity, and managing environmental stresses. Besides, this pathway plays an important role in the pathogenesis of common inflammatory skin diseases such as allergic contact dermatitis, atopic dermatitis, and psoriasis. Therefore, the present review highlights the crucial role of Nrf2 in KCs for maintaining skin homeostasis and regulating skin immunity, as well as its contribution to the pathophysiology of inflammatory skin diseases. Finally, a particular emphasis will be placed on the therapeutic potential of targeting the Nrf2 pathway to alleviate symptoms of these inflammatory skin disorders.
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Affiliation(s)
- Sara Salman
- Université Paris‐Saclay, INSERM, Inflammation, Microbiome and ImmunosurveillanceOrsayFrance
| | - Virginie Paulet
- Université Paris‐Saclay, INSERM, Inflammation, Microbiome and ImmunosurveillanceOrsayFrance
| | - Kévin Hardonnière
- Université Paris‐Saclay, INSERM, Inflammation, Microbiome and ImmunosurveillanceOrsayFrance
| | - Saadia Kerdine‐Römer
- Université Paris‐Saclay, INSERM, Inflammation, Microbiome and ImmunosurveillanceOrsayFrance
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Tan TT, Lai RC, Sim WK, Zhang B, Lim SK. Enhancing EV-cell communication through "External Modulation of Cell by EV" (EMCEV). Cytotherapy 2025; 27:1-6. [PMID: 39177523 DOI: 10.1016/j.jcyt.2024.07.014] [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: 05/15/2024] [Revised: 07/21/2024] [Accepted: 07/22/2024] [Indexed: 08/24/2024]
Abstract
Mesenchymal stem/stromal cells (MSC) have displayed promising therapeutic potential. Nonetheless, no United States Food and Drug Administration (FDA)-approved MSC product exists due largely to the absence of a reliable potency assay based on the mechanisms of action to ensure consistent efficacy. MSCs are now thought to exert their effects primarily by releasing small extracellular vesicles (sEVs) of 50-200 nm. While non-living MSC-sEV drugs offer distinct advantages over larger, living MSC drugs, elucidating their mechanism of action to develop robust potency assays remains a challenge. A pivotal prelude to elucidating the mechanism of action for MSC-sEVs is how extracellular vesicles (EVs) engage their primary target cells. Given the inherent inefficiencies of processes such as endocytosis, endosomal escape and EV uncoating during cellular internalization, we propose an alternative EV-cell engagement: EMCEV (Extracellular Modulation of Cells by EV). This approach involves extracellular modulation by EV attributes to generate signaling/inhibitory molecules that have the potential to affect many cells within the vicinity, thereby eliciting a more widespread tissue response.
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Affiliation(s)
| | | | | | - Bin Zhang
- Paracrine Therapeutics Pte. Ltd., Singapore
| | - Sai Kiang Lim
- Paracrine Therapeutics Pte. Ltd., Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Republic of Singapore.
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Pan Y, Wang Y, Xu M, Zhong M, Peng X, Zeng K, Huang X. The Roles of Innate Immune Cells in Atopic Dermatitis. J Innate Immun 2024; 16:385-396. [PMID: 39025048 PMCID: PMC11324229 DOI: 10.1159/000539534] [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: 03/01/2024] [Accepted: 05/23/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by recurrent eczematous lesions and severe pruritus. The economic burden and time penalty caused by the relapse of AD reduce patients' life quality. SUMMARY AD has complex pathogenesis, including genetic disorders, epidermal barrier dysfunction, abnormal immune responses, microbial dysbiosis of the skin, and environmental factors. Recently, the role of innate immune cells in AD has attracted considerable attention. This review highlighted recent findings on innate immune cells in the onset and progression of AD. KEY MESSAGES Innate immune cells play essential roles in the pathogenesis of AD and enough attention should be given for treating AD from the perspective of innate immunity in clinics.
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Affiliation(s)
- Yuke Pan
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Youyi Wang
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Meinian Xu
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Meizhen Zhong
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoming Peng
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Kang Zeng
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaowen Huang
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Chen Z, Dragan M, Sun P, Haensel D, Vu R, Cui L, Shi Y, Dai X. An AhR-Ovol1-Id1 regulatory axis in keratinocytes promotes skin homeostasis against atopic dermatitis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.29.577821. [PMID: 38352592 PMCID: PMC10862726 DOI: 10.1101/2024.01.29.577821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
Skin is our outer permeability and immune defense barrier against myriad external assaults. Aryl hydrocarbon receptor (AhR) senses environmental factors and regulates barrier robustness and immune homeostasis. AhR agonist is in clinical trial for atopic dermatitis (AD) treatment, but the underlying mechanism of action remains ill-defined. Here we report OVOL1/Ovol1 as a conserved and direct transcriptional target of AhR in epidermal keratinocytes. We show that OVOL1/Ovol1 impacts AhR regulation of keratinocyte gene expression, and Ovol1 deletion in keratinocytes hampers AhR's barrier promotion function and worsens AD-like inflammation. Mechanistically, we identify Ovol1's direct downstream targets genome-wide, and provide in vivo evidence for Id1's critical role in barrier maintenance and disease suppression. Furthermore, our findings reveal an IL-1/dermal γδT cell axis exacerbating both type 2 and type 3 immune responses downstream of barrier perturbation in Ovol1 -deficient AD skin. Finally, we present data suggesting the clinical relevance of OVOL1 and ID1 function in human AD. Our study highlights a keratinocyte-intrinsic AhR-Ovol1-Id1 regulatory axis that promotes both epidermal and immune homeostasis against AD-like inflammation, implicating new therapeutic targets for AD.
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Stănescu AMA, Cristea AMA, Bejan GC, Vieru M, Simionescu AA, Popescu FD. Allergic Contact Cell-Mediated Hypersensitivity in Psoriasis: A Narrative Minireview. Medicina (B Aires) 2022; 58:914. [PMID: 35888633 PMCID: PMC9324524 DOI: 10.3390/medicina58070914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 11/17/2022] Open
Abstract
The dysfunctionality of the protective skin barrier in psoriasis allows easier cutaneous penetration of various contact haptens; thus, such patients can develop allergic contact hypersensitivity as a comorbidity. Both skin conditions involve T-cell-mediated mechanisms. Dermatologists and allergists should consider assessing allergic contact cell-mediated hypersensitivity in selected psoriasis patients, especially those with palmoplantar psoriasis and who are refractory to topical treatments, and in patients with psoriasis, with or without arthritis, treated with biologics that present skin lesions clinically suggestive of contact dermatitis.
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Affiliation(s)
| | - Ana-Maria-Antoaneta Cristea
- Department of Allergology and Clinical Immunology, Nicolae Malaxa Clinical Hospital, 022441 Bucharest, Romania; (A.-M.-A.C.); (F.-D.P.)
| | - Gabriel Cristian Bejan
- Department of Family Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Mariana Vieru
- Department of Allergology and Clinical Immunology, Nicolae Malaxa Clinical Hospital, 022441 Bucharest, Romania; (A.-M.-A.C.); (F.-D.P.)
- Department of Allergology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Anca Angela Simionescu
- Department of Obstetrics and Gynecology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Department of Obstetrics and Gynecology, Filantropia Clinical Hospital, 011132 Bucharest, Romania
| | - Florin-Dan Popescu
- Department of Allergology and Clinical Immunology, Nicolae Malaxa Clinical Hospital, 022441 Bucharest, Romania; (A.-M.-A.C.); (F.-D.P.)
- Department of Allergology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
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Schmidt V, Hogan AE, Fallon PG, Schwartz C. Obesity-Mediated Immune Modulation: One Step Forward, (Th)2 Steps Back. Front Immunol 2022; 13:932893. [PMID: 35844529 PMCID: PMC9279727 DOI: 10.3389/fimmu.2022.932893] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 05/27/2022] [Indexed: 11/15/2022] Open
Abstract
Over the past decades, the relationship between the immune system and metabolism has become a major research focus. In this arena of immunometabolism the capacity of adipose tissue to secrete immunomodulatory molecules, including adipokines, within the underlying low-grade inflammation during obesity brought attention to the impact obesity has on the immune system. Adipokines, such as leptin and adiponectin, influence T cell differentiation into different T helper subsets and their activation during immune responses. Furthermore, within the cellular milieu of adipose tissue nutrient availability regulates differentiation and activation of T cells and changes in cellular metabolic pathways. Upon activation, T cells shift from oxidative phosphorylation to oxidative glycolysis, while the differential signaling of the kinase mammalian target of rapamycin (mTOR) and the nuclear receptor PPARγ, amongst others, drive the subsequent T cell differentiation. While the mechanisms leading to a shift from the typical type 2-dominated milieu in lean people to a Th1-biased pro-inflammatory environment during obesity are the subject of extensive research, insights on its impact on peripheral Th2-dominated immune responses become more evident. In this review, we will summarize recent findings of how Th2 cells are metabolically regulated during obesity and malnutrition, and how these states affect local and systemic Th2-biased immune responses.
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Affiliation(s)
- Viviane Schmidt
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Andrew E. Hogan
- Kathleen Lonsdale Human Health Institute, Maynooth University, Maynooth, Ireland
- Obesity Immunology Research, St. Vincent’s University Hospital and University College Dublin, Dublin, Ireland
| | - Padraic G. Fallon
- Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Christian Schwartz
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Medical Immunology Campus Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- *Correspondence: Christian Schwartz,
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Hawerkamp HC, Fahy CMR, Fallon PG, Schwartz C. Break on through: The role of innate immunity and barrier defence in atopic dermatitis and psoriasis. SKIN HEALTH AND DISEASE 2022; 2:e99. [PMID: 35677926 PMCID: PMC9168024 DOI: 10.1002/ski2.99] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 01/07/2022] [Accepted: 01/23/2022] [Indexed: 12/20/2022]
Abstract
The human skin can be affected by a multitude of diseases including inflammatory conditions such as atopic dermatitis and psoriasis. Here, we describe how skin barrier integrity and immunity become dysregulated during these two most common inflammatory skin conditions. We summarise recent advances made in the field of the skin innate immune system and its interaction with adaptive immunity. We review gene variants associated with atopic dermatitis and psoriasis that affect innate immune mechanisms and skin barrier integrity. Finally, we discuss how current and future therapies may affect innate immune responses and skin barrier integrity in a generalized or more targeted approach in order to ameliorate disease in patients.
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Affiliation(s)
- H C Hawerkamp
- Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin Dublin Ireland
| | - C M R Fahy
- Paediatric Dermatology Children's Health Ireland at Crumlin Dublin Ireland.,Royal United Hospitals NHS Foundation Trust Bath UK
| | - P G Fallon
- Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin Dublin Ireland.,National Children's Research Centre Our Lady's Children's Hospital Dublin Ireland.,Clinical Medicine Trinity College Dublin Dublin Ireland
| | - C Schwartz
- Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin Dublin Ireland.,Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg Erlangen Germany.,Medical Immunology Campus Erlangen FAU Erlangen-Nürnberg Erlangen Germany
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DISORDERS OF INNATE IMMUNITY IN VARIOUS FORMS OF THE CHRONIC ECZEMA. WORLD OF MEDICINE AND BIOLOGY 2022. [DOI: 10.26724/2079-8334-2022-3-81-99-103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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