|
1
|
Glinka DM, MacGregor GG. The PAR2 Antagonist Larazotide Can Mitigate Acute Histamine-Stimulated Epithelial Barrier Disruption in Keratinocytes: A Potential Adjunct Treatment for Atopic Dermatitis. JID INNOVATIONS 2025; 5:100369. [PMID: 40330848 PMCID: PMC12051560 DOI: 10.1016/j.xjidi.2025.100369] [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: 12/15/2023] [Revised: 03/24/2025] [Accepted: 03/24/2025] [Indexed: 05/08/2025] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin condition with evidence of defects in the barrier properties of the epidermis. Changes in the permeability properties of the tight junction have been reported in AD, and reversing this leaky tight junction may be a potential treatment for AD. This study aimed to determine the effect of larazotide, an antagonist of the protease-activated receptor 2, on the permeability and barrier properties of the tight junctions in keratinocyte monolayers. Normal human epithelial keratinocytes were grown in culture on permeable supports. The effects of larazotide on transepithelial resistance and permeability properties of keratinocyte monolayers were studied before and after histamine challenge. Larazotide mitigated the disruptive effect of histamine on epithelial permeability by increasing the electrical resistance and decreasing epithelial permeability. Larazotide may be beneficial as a topical therapeutic for AD; however, the permeability properties of the short-peptide larazotide through the uppers layers of the epidermis is currently unknown. In conclusion, the protease-activated receptor 2 antagonist larazotide has a protective effect on keratinocyte monolayers and may be useful as an adjunct therapeutic agent to enhance barrier function and promote epidermal healing in AD.
Collapse
Affiliation(s)
| | - Gordon G. MacGregor
- Alabama College of Osteopathic Medicine, Dothan, Alabama, USA
- Orlando College of Osteopathic Medicine, Winter Garden, Florida, USA
- Yogalytes LLC, Huntsville, Alabama, USA
| |
Collapse
|
|
2
|
Principato S, DeVries ZC. Effects of aging and cleaning on bed bug (Hemiptera: Cimicidae)-derived histamine. JOURNAL OF MEDICAL ENTOMOLOGY 2025; 62:495-500. [PMID: 40221908 PMCID: PMC12076141 DOI: 10.1093/jme/tjaf042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/25/2025] [Accepted: 03/03/2025] [Indexed: 04/15/2025]
Abstract
Bed bugs (Cimex lectularius L.) are common indoor pests found in close association with humans. Bed bug feces have been identified as the primary source of indoor environmental histamine, an emerging contaminant that could pose a potential threat to human health. Therefore, it is critical that we understand the stability of histamine in homes, along with mitigation strategies so that we can reduce exposure and potential health risks. In this study we characterized histamine stability over time on 2 surfaces (unfinished wood, fabric), discovering that aging histamine at room temperature, over the course of 9 mo, showed no significant changes in the level of this biogenic amine. As histamine appears slow to degrade on its own, we evaluated the efficacy of various cleaning methods for reducing or removing histamine from these surfaces. The most effective histamine cleaning methods on fabric were bleach, hydrogen peroxide, and a laundry cycle, while multi-purpose cleaner, bleach, and hydrogen peroxide were the most effective on unfinished wood. Overall, histamine reduction was most influenced by more aggressive cleaning methods (hard scrubbing) or cleaners known for removing stains (hydrogen peroxide, bleach). The results of this study will enhance our ability to reduce exposure to this emerging contaminant.
Collapse
Affiliation(s)
- Simona Principato
- Department of Entomology, University of Kentucky, Lexington, KY, USA
| | - Zachary C DeVries
- Department of Entomology, University of Kentucky, Lexington, KY, USA
| |
Collapse
|
|
3
|
Ma H, Liu F, Fang Y. Andrographolide represses HIF-1α and VEGFA expression, thus inhibiting hypoxia-induced proliferation, oxidative stress, and inflammatory cytokine secretion in human keratinocytes. Mol Immunol 2025; 180:23-32. [PMID: 39987641 DOI: 10.1016/j.molimm.2025.02.013] [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: 03/23/2024] [Revised: 01/03/2025] [Accepted: 02/19/2025] [Indexed: 02/25/2025]
Abstract
Epidermal hypoxia, hyperproliferation of keratinocytes, and inflammation in skin lesions are relevant to the pathogenesis of inflammatory skin diseases, including psoriasis. Andrographolide (Andro) is a natural labdane diterpene with diverse biofunctions. Andro has been reported to alleviate psoriasis in mice. However, the exact mechanisms need further study. Our results demonstrated that Andro inhibited hypoxia-induced proliferation of human keratinocytes. Andro also protected the keratinocytes from hypoxia-induced oxidative stress and inflammatory response. Furthermore, we found that Andro suppressed the expression of HIF-1α and VEGFA expression in hypoxia-exposed keratinocytes. Overexpression of either HIF-1α or VEGFA attenuated the inhibitory effects of Andro on hypoxia-induced proliferation, oxidative stress, and inflammatory cytokine secretion. In summary, our results demonstrated that Andro protected keratinocytes from hypoxia-induced proliferation, oxidative stress, and inflammatory cytokine secretion by suppressing HIF-1α and VEGFA expression. Our findings provide an unreported insight into the potential use of Andro as an effective agent for the treatment of inflammatory skin diseases such as psoriasis in the future.
Collapse
Affiliation(s)
- Hui Ma
- Department of Dermatology, Nanyang First People's Hospital, Nanyang 473004, China
| | - Fu Liu
- Department of General Surgery, Nanyang First People's Hospital, Nanyang 473004, China
| | - Youhua Fang
- Department of Dermatology, Chun'an First People's Hospital, Hangzhou 311700, China.
| |
Collapse
|
|
4
|
Dong XQ, Zhang YH, Luo J, Li MJ, Ma LQ, Qi YT, Miao YL. Keratin 1 modulates intestinal barrier and immune response via kallikrein kinin system in ulcerative colitis. World J Gastroenterol 2025; 31:102070. [PMID: 39958441 PMCID: PMC11752705 DOI: 10.3748/wjg.v31.i6.102070] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/06/2024] [Accepted: 12/19/2024] [Indexed: 01/10/2025] Open
Abstract
BACKGROUND External factors in ulcerative colitis (UC) exacerbate colonic epithelial permeability and inflammatory responses. Keratin 1 (KRT1) is crucial in regulating these alterations, but its specific role in the progression of UC remains to be fully elucidated. AIM To explore the role and mechanisms of KRT1 in the regulation of colonic epithelial permeability and inflammation in UC. METHODS A KRT1 antibody concentration gradient test, along with a dextran sulfate sodium (DSS)-induced animal model, was implemented to investigate the role of KRT1 in modulating the activation of the kallikrein kinin system (KKS) and the cleavage of bradykinin (BK)/high molecular weight kininogen (HK) in UC. RESULTS Treatment with KRT1 antibody in Caco-2 cells suppressed cell proliferation, induced apoptosis, reduced HK expression, and increased BK expression. It further downregulated intestinal barrier proteins, including occludin, zonula occludens-1, and claudin, and negatively impacted the coagulation factor XII. These changes led to enhanced activation of BK and HK cleavage, thereby intensifying KKS-mediated inflammation in UC. In the DSS-induced mouse model, administration of KRT1 antibody mitigated colonic injury, increased colon length, alleviated weight loss, and suppressed inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-α. It also facilitated repair of the intestinal barrier, reducing DSS-induced injury. CONCLUSION KRT1 inhibits BK expression, suppresses inflammatory cytokines, and enhances markers of intestinal barrier function, thus ameliorating colonic damage and maintaining barrier integrity. KRT1 is a viable therapeutic target for UC.
Collapse
Affiliation(s)
- Xiang-Qian Dong
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Ying-Hui Zhang
- Department of Gastroenterology, Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan Province, China
| | - Juan Luo
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Mao-Juan Li
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Lan-Qing Ma
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Ya-Ting Qi
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Ying-Lei Miao
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| |
Collapse
|
|
5
|
Zhang J, Li G, Guo Q, Yang Y, Yang J, Feng X, Yao Z. Allergens in Atopic Dermatitis. Clin Rev Allergy Immunol 2025; 68:11. [PMID: 39924626 DOI: 10.1007/s12016-025-09024-7] [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: 01/20/2025] [Indexed: 02/11/2025]
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex relationship to allergens. While AD itself is not an allergic reaction and does not necessarily involve allergen sensitization, AD patients show higher rates of sensitization to food and inhalant allergens compared to the general population. Recent evidence refining the "dual allergen exposure hypothesis" demonstrates that early oral exposure to allergens through an intact gastrointestinal barrier typically promotes tolerance, while exposure through compromised skin or respiratory barriers often leads to sensitization. Therefore, the impaired skin barrier function in AD patients increases the risk of transcutaneous sensitization and may interfere with oral tolerance development. Interestingly, AD patients' sensitivity to contact allergens (such as metals and fragrances) is not necessarily higher than that of the general population, which may be related to the inherent properties of these allergens. Personalized allergen testing can help guide appropriate allergen avoidance and reintroduction strategies in AD management. The insights into optimal allergen exposure conditions have also expanded the potential applications of allergen-specific immunotherapy in preventing AD onset in high-risk populations and halting the atopic march.
Collapse
Affiliation(s)
- Jiayan Zhang
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Guofang Li
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Qiuyang Guo
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yijun Yang
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Jinxiang Yang
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Xiaobo Feng
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Zhirong Yao
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
| |
Collapse
|
|
6
|
Missaoui S, Gaadi A, Oussama K, Adam Z, Bousfiha AA, Hali F. The primary mechanisms underlying atopic dermatitis. LA TUNISIE MEDICALE 2025; 103:65-72. [PMID: 39812196 PMCID: PMC11906244 DOI: 10.62438/tunismed.v103i1.5220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 10/23/2024] [Indexed: 01/16/2025]
Abstract
INTRODUCTION Atopic dermatitis (AD) is a complex skin disease frequently linked with other atopic symptoms such allergic rhinitis and asthma. The disease's history consists of persistent relapses with extreme pruritus, which lowers quality of life. AD has become a global health concern as its incidence has increased over the last few decades. It ranks as the third most common dermatologic disorder. AIM There are several open questions about the mechanisms underlying atopic dermatitis (AD), This review aims to emphasize the recent advances in scientific research regarding the pathophysiologic mechanism of AD and the clinical application of these factors. METHODS A PubMed search was performed using the keywords "Atopic Dermatitis (AD)", "epidemiology", "clinical presentation", "diagnosis", "pathophysiology", "genetic defect", "impaired skin barrier", "immune dysregulation". The search strategy included meta-analyses, clinical trial, observational studies, and reviews. RESULTS Atopic dermatitis affects over 2 million children worldwide, with a lifetime incidence of up to 20%. New data suggest that its incidence is still growing, particularly in low-income nations. AD is diagnosed clinically using the patient's medical history, particular clinical symptoms, and the elimination of other non-inflammatory skin conditions. The pathogenesis of AD is extremely complicated and involves several etiologies, including genetics, the microbiome, abnormalities in the skin barrier, along with dysfunctional innate and adaptive immune systems. CONCLUSION Recent research has improved our understanding of disease pathophysiology in atopic dermatitis. Current and future clinical trials are expected to continue clarifying this complex and heterogeneous skin disease, and to develop medications that promise more effective therapy, particularly for individuals with limited response to conventional treatments.
Collapse
Affiliation(s)
- Sara Missaoui
- Laboratory of Clinical Immunology, Inflammation and Allergy, Hassan II University, Faculty of Medicine and Pharmacy of Casablanca, Morocco
| | - Asmaa Gaadi
- Laboratory of Clinical Immunology, Inflammation and Allergy, Hassan II University, Faculty of Medicine and Pharmacy of Casablanca, Morocco
| | - Khaoula Oussama
- Laboratory of Clinical Immunology, Inflammation and Allergy, Hassan II University, Faculty of Medicine and Pharmacy of Casablanca, Morocco
| | - Zahra Adam
- Laboratory of Clinical Immunology, Inflammation and Allergy, Hassan II University, Faculty of Medicine and Pharmacy of Casablanca, Morocco
| | - Ahmed Aziz Bousfiha
- Laboratory of Clinical Immunology, Inflammation and Allergy, Hassan II University, Faculty of Medicine and Pharmacy of Casablanca, Morocco
| | - Fouzia Hali
- Dermatology department, CHU Ibn Rochd, Hassan II University, Faculty of Medicine and Pharmacy, Casablanca, Morocco
| |
Collapse
|
|
7
|
Zhang W, Lei J, Jiang P, Hao T, Yuan Y, Hu H, Li W. Double-Layered Microneedle Patch Integrated with Multifunctional Nanoparticles and Live Bacteria for Long-Term Treatment of Atopic Dermatitis. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2409121. [PMID: 39544127 DOI: 10.1002/smll.202409121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 11/06/2024] [Indexed: 11/17/2024]
Abstract
Atopic dermatitis (AD) is a complex and prevalent chronic inflammatory skin disease that impacts a significant portion of the global population. Conventional treatments often focus on a singular pathogenic factor or suffer from limited skin penetration, resulting in unsatisfactory outcomes. Here, a multifunctional double-layered microneedle (MN) patch is proposed for long-term and effective treatment of AD by integrating therapeutic nanoparticles (NPs) and live bacteria. In the design, the MN tips are loaded with Prussian blue NPs encapsulating cetirizine hydrochloride (CET@PB NPs), while the patch backing incorporates Bacillus subtilis (B. subtilis). Upon skin insertion, the MN patch efficiently delivers CET@PB NPs into the skin and deposits live B. subtilis on the skin surface after fast dissolution. The delivered NPs not only scavenge reactive oxygen species (ROS) and improve oxidative stress microenvironments in the AD lesions, but also provide sustained release of the antihistamine CET in the skin for alleviating AD symptoms. Furthermore, B. subtilis survives on the skin for over 9 days and effectively inhibits the growth of the harmful bacteria Staphylococcus aureus. These features highlight the superior efficacy of the MN patch in long-term treatment of AD, offering a promising alternative for the management of skin disorders in clinics.
Collapse
Affiliation(s)
- Wen Zhang
- Department of Stomatology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China
| | - Jiapeng Lei
- Department of Stomatology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China
| | - Peng Jiang
- Department of Stomatology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China
| | - Tianshu Hao
- Department of Stomatology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China
| | - Yaqi Yuan
- Department of Stomatology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China
| | - Hankun Hu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China
| | - Wei Li
- Department of Stomatology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China
- TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China
| |
Collapse
|
|
8
|
Scholaert M, Peries M, Braun E, Martin J, Serhan N, Loste A, Bruner A, Basso L, Chaput B, Merle E, Descargues P, Pagès E, Gaudenzio N. Multimodal profiling of biostabilized human skin modules reveals a coordinated ecosystem response to injected mRNA-1273 COVID-19 vaccine. Allergy 2024; 79:3341-3359. [PMID: 39157907 PMCID: PMC11657073 DOI: 10.1111/all.16273] [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: 12/14/2023] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 08/20/2024]
Abstract
BACKGROUND The field of drug development is witnessing a remarkable surge in the development of innovative strategies. There is a need to develop technological platforms capable of generating human data prior to progressing to clinical trials. METHODS Here we introduce a new flexible solution designed for the comprehensive monitoring of the natural human skin ecosystem's response to immunogenic drugs over time. Based on unique bioengineering to preserve surgical resections in a long survival state, it allows for the first time a comprehensive analysis of resident immune cells response at both organ and single-cell levels. RESULTS Upon injection of the mRNA-1273 COVID-19 vaccine, we characterized precise sequential molecular events triggered upon detection of the exogenous substance. The vaccine consistently targets DC/macrophages and mast cells, regardless of the administration route, while promoting specific cell-cell communications in surrounding immune cell subsets. CONCLUSION Given its direct translational relevance, this approach provides a multiscale vision of genuine human tissue immunity that could pave the way toward the development of new vaccination and drug development strategies.
Collapse
Affiliation(s)
- Manon Scholaert
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291—CNRS UMR5051University Toulouse IIIToulouseFrance
- Genoskin SASToulouseFrance
| | | | | | - Jeremy Martin
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291—CNRS UMR5051University Toulouse IIIToulouseFrance
| | - Nadine Serhan
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291—CNRS UMR5051University Toulouse IIIToulouseFrance
| | - Alexia Loste
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291—CNRS UMR5051University Toulouse IIIToulouseFrance
| | - Audrey Bruner
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291—CNRS UMR5051University Toulouse IIIToulouseFrance
| | - Lilian Basso
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291—CNRS UMR5051University Toulouse IIIToulouseFrance
| | - Benoît Chaput
- Department of Plastic, Reconstructive and Aesthetic Surgery, Rangueil HospitalCHU ToulouseToulouseFrance
| | | | | | | | - Nicolas Gaudenzio
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291—CNRS UMR5051University Toulouse IIIToulouseFrance
- Genoskin SASToulouseFrance
| |
Collapse
|
|
9
|
Sun N, Ogulur I, Mitamura Y, Yazici D, Pat Y, Bu X, Li M, Zhu X, Babayev H, Ardicli S, Ardicli O, D'Avino P, Kiykim A, Sokolowska M, van de Veen W, Weidmann L, Akdis D, Ozdemir BG, Brüggen MC, Biedermann L, Straumann A, Kreienbühl A, Guttman-Yassky E, Santos AF, Del Giacco S, Traidl-Hoffmann C, Jackson DJ, Wang DY, Lauerma A, Breiteneder H, Zhang L, O'Mahony L, Pfaar O, O'Hehir R, Eiwegger T, Fokkens WJ, Cabanillas B, Ozdemir C, Kistler W, Bayik M, Nadeau KC, Torres MJ, Akdis M, Jutel M, Agache I, Akdis CA. The epithelial barrier theory and its associated diseases. Allergy 2024; 79:3192-3237. [PMID: 39370939 DOI: 10.1111/all.16318] [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: 05/17/2024] [Revised: 08/28/2024] [Accepted: 09/03/2024] [Indexed: 10/08/2024]
Abstract
The prevalence of many chronic noncommunicable diseases has been steadily rising over the past six decades. During this time, over 350,000 new chemical substances have been introduced to the lives of humans. In recent years, the epithelial barrier theory came to light explaining the growing prevalence and exacerbations of these diseases worldwide. It attributes their onset to a functionally impaired epithelial barrier triggered by the toxicity of the exposed substances, associated with microbial dysbiosis, immune system activation, and inflammation. Diseases encompassed by the epithelial barrier theory share common features such as an increased prevalence after the 1960s or 2000s that cannot (solely) be accounted for by the emergence of improved diagnostic methods. Other common traits include epithelial barrier defects, microbial dysbiosis with loss of commensals and colonization of opportunistic pathogens, and circulating inflammatory cells and cytokines. In addition, practically unrelated diseases that fulfill these criteria have started to emerge as multimorbidities during the last decades. Here, we provide a comprehensive overview of diseases encompassed by the epithelial barrier theory and discuss evidence and similarities for their epidemiology, genetic susceptibility, epithelial barrier dysfunction, microbial dysbiosis, and tissue inflammation.
Collapse
Affiliation(s)
- Na Sun
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, P. R. China
| | - Ismail Ogulur
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Yasutaka Mitamura
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Duygu Yazici
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Yagiz Pat
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Xiangting Bu
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Manru Li
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Xueyi Zhu
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Huseyn Babayev
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Sena Ardicli
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
- Department of Genetics, Faculty of Veterinary Medicine, Bursa Uludag University, Bursa, Turkey
| | - Ozge Ardicli
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
- Division of Food Processing, Milk and Dairy Products Technology Program, Karacabey Vocational School, Bursa Uludag University, Bursa, Turkey
| | - Paolo D'Avino
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Ayca Kiykim
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
- Department of Pediatrics, Division of Pediatric Allergy and Immunology, Cerrahpasa School of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Milena Sokolowska
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Willem van de Veen
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Lukas Weidmann
- Department of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Deniz Akdis
- Department of Cardiology, University Hospital Zurich, Zurich, Switzerland
| | | | - Marie Charlotte Brüggen
- Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | - Luc Biedermann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Alex Straumann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Andrea Kreienbühl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Emma Guttman-Yassky
- Department of Dermatology, and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alexandra F Santos
- Department of Women and Children's Health (Pediatric Allergy), School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
- Children's Allergy Service, Evelina London Children's Hospital, Guy's and St. Thomas' Hospital, London, UK
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Stefano Del Giacco
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | | | - David J Jackson
- Guy's Severe Asthma Centre, Guy's Hospital, Guy's & St Thomas' NHS Trust, London, UK
- School of Immunology & Microbial Sciences, King's College London, London, UK
| | - De-Yun Wang
- Department of Otolaryngology, Infectious Diseases Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore City, Singapore
| | - Antti Lauerma
- Department of Dermatology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Heimo Breiteneder
- Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria
| | - Luo Zhang
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- Beijing Laboratory of Allergic Diseases and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, China
| | - Liam O'Mahony
- Department of Medicine and School of Microbiology, University College Cork, Cork, Ireland
- APC Microbiome Ireland, Cork, Ireland
| | - Oliver Pfaar
- Department of Otorhinolaryngology, Head and Neck Surgery, Section of Rhinology and Allergy, University Hospital Marburg, Philipps-Universität Marburg, Marburg, Germany
| | - Robyn O'Hehir
- Allergy, Asthma & Clinical Immunology, The Alfred Hospital, Melbourne, Victoria, Australia
- Department of Immunology, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia
| | - Thomas Eiwegger
- Translational Medicine Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
- Department of Pediatric and Adolescent Medicine, University Hospital St. Pölten, St. Pölten, Austria
| | - Wytske J Fokkens
- Department of Otorhinolaryngology & Head and Neck Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Beatriz Cabanillas
- Department of Allergy, Instituto de Investigación Biosanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Cevdet Ozdemir
- Department of Pediatric Basic Sciences, Institute of Child Health, Istanbul University, Istanbul, Turkey
- Istanbul Faculty of Medicine, Department of Pediatrics, Division of Pediatric Allergy and Immunology, Istanbul University, Istanbul, Turkey
| | - Walter Kistler
- Department of Sports Medicine, Davos Hospital, Davos, Switzerland
- Swiss Research Institute for Sports Medicine (SRISM), Davos, Switzerland
- Medical Committee International Ice Hockey Federation (IIHF), Zurich, Switzerland
| | - Mahmut Bayik
- Department of Internal Medicine and Hematology, Marmara University, Istanbul, Turkey
| | - Kari C Nadeau
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Maria J Torres
- Allergy Unit, IBIMA-Hospital Regional Universitario de Málaga-ARADyAL, UMA, Málaga, Spain
| | - Mübeccel Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Marek Jutel
- Department of Clinical Immunology, Wrocław Medical University, Wroclaw, Poland
| | - Ioana Agache
- Faculty of Medicine, Department of Allergy and Clinical Immunology, Transylvania University, Brasov, Romania
| | - Cezmi A Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| |
Collapse
|
|
10
|
Cervantes Recalde MF, Schmidt J, Girardi C, Massironi M, Rechl ML, Hans J, Stuhlmann D, Somoza V, Lieder B. Capsaicin attenuates the effect of inflammatory cytokines in a HaCaT cell model for basal keratinocytes. Front Pharmacol 2024; 15:1474898. [PMID: 39469627 PMCID: PMC11513304 DOI: 10.3389/fphar.2024.1474898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 09/25/2024] [Indexed: 10/30/2024] Open
Abstract
Introduction The resolution of the skin's inflammatory response is only possible if its barrier function is restored. TRPV1 channel activation plays an important role during inflammation but the effect of this activation on the skin barrier under inflammatory conditions has not been clarified. We hypothesize that it could potentially aid the keratinocyte barrier by reducing inflammatory cytokine release and promoting tight junction development. Methods To explore the role of TRPV1 activation in inflammation, we designed and optimized an in vitro model of keratinocytes with basal epidermal layer characteristics using HaCaT cells and TNFα to induce inflammation. Results TNFα increased the gene expression of tight junction protein claudin 1 (CLDN1) by at least 2.60 ± 0.16-fold, in a concentration-dependent manner, over a 48 h period. The administration of a capsaicin pre-treatment reduced the CLDN1 expression to 1.51 ± 0.16-fold during the first 6 h after TNFα induction, whereas IL-8 cytokine release was reduced 0.64 ± 0.17-fold. After 48 h, CLDN1 protein levels increased by a factor of 6.57 ± 1.39 compared to cells only treated with TNFα. Discussion These results suggest that activation of TRPV1 by capsaicin can potentiate the increase in CLDN1 expression and CLDN1 protein synthesis induced by TNFα in cultured keratinocytes, while reducing the release of IL-8.
Collapse
Affiliation(s)
- Maria Fernanda Cervantes Recalde
- Institute of Physiological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
- Vienna Doctoral School in Chemistry (DoSChem), University of Vienna, Vienna, Austria
| | - Jana Schmidt
- Institute of Physiological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
| | | | | | - Markus Leo Rechl
- Institute of Physiological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
- Vienna Doctoral School in Chemistry (DoSChem), University of Vienna, Vienna, Austria
- Christian Doppler Laboratory for Taste Research, Faculty of Chemistry, University of Vienna, Vienna, Austria
| | | | | | - Veronika Somoza
- Institute of Physiological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
- Leibniz Institute of Food Systems Biology, Technical University of Munich, Freising, Germany
| | - Barbara Lieder
- Institute of Physiological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria
- Christian Doppler Laboratory for Taste Research, Faculty of Chemistry, University of Vienna, Vienna, Austria
- Institute of Clinical Nutrition, University of Hohenheim, Stuttgart, Germany
| |
Collapse
|
|
11
|
Chen J, Liu C, Yang Y, Gong X, Qian H. The stratum corneum barrier: impaired function in relation to associated lipids and proteins. Tissue Barriers 2024:2361197. [PMID: 38818698 DOI: 10.1080/21688370.2024.2361197] [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: 04/03/2024] [Accepted: 05/23/2024] [Indexed: 06/01/2024] Open
Abstract
The skin is the largest organ of the human body and is widely considered to be the first-line defense of the body, providing essential protection against mechanical, physical, and chemical damage. Keratinocytes are the primary cells of the outer layer of the epidermis, which acts as a mechanical and permeability barrier. The epidermis is a permanently renewed tissue where undifferentiated keratinocytes located at the basal layer proliferate and migrate to the overlying layers. Here we report that some components of keratinocytes affect the formation and differentiation of the stratum corneum, which is the most specialized layer of the epidermis.
Collapse
Affiliation(s)
- Jie Chen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, Xuhui, District, China
| | - Changjie Liu
- SIMPLY THIS Skin Ecology Research Institute, Shili (Shanghai) Biotechology Co., Ltd, Shanghai, China
| | - Yuan Yang
- SIMPLY THIS Skin Ecology Research Institute, Shili (Shanghai) Biotechology Co., Ltd, Shanghai, China
| | - Xue Gong
- SIMPLY THIS Skin Ecology Research Institute, Shili (Shanghai) Biotechology Co., Ltd, Shanghai, China
| | - Huan Qian
- Department of Plastic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
12
|
Quadri M, Baudouin C, Lotti R, Palazzo E, Campanini L, Bernard FX, Bellemere G, Pincelli C, Marconi A. Characterization of Skin Interfollicular Stem Cells and Early Transit Amplifying Cells during the Transition from Infants to Young Children. Int J Mol Sci 2024; 25:5635. [PMID: 38891823 PMCID: PMC11171949 DOI: 10.3390/ijms25115635] [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: 03/25/2024] [Revised: 05/16/2024] [Accepted: 05/17/2024] [Indexed: 06/21/2024] Open
Abstract
In the interfollicular epidermis, keratinocyte stem cells (KSC) generate a short-lived population of transit amplifying (TA) cells that undergo terminal differentiation after several cell divisions. Recently, we isolated and characterized a highly proliferative keratinocyte cell population, named "early" TA (ETA) cell, representing the first KSC progenitor with exclusive features. This work aims to evaluate epidermis, with a focus on KSC and ETA cells, during transition from infancy to childhood. Reconstructed human epidermis (RHE) generated from infant keratinocytes is more damaged by UV irradiation, as compared to RHE from young children. Moreover, the expression of several differentiation and barrier genes increases with age, while the expression of genes related to stemness is reduced from infancy to childhood. The proliferation rate of KSC and ETA cells is higher in cells derived from infants' skin samples than of those derived from young children, as well as the capacity of forming colonies is more pronounced in KSC derived from infants than from young children's skin samples. Finally, infants-KSC show the greatest regenerative capacity in skin equivalents, while young children ETA cells express higher levels of differentiation markers, as compared to infants-ETA. KSC and ETA cells undergo substantial changes during transition from infancy to childhood. The study presents a novel insight into pediatric skin, and sheds light on the correlation between age and structural maturation of the skin.
Collapse
Affiliation(s)
- Marika Quadri
- DermoLab, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (M.Q.); (E.P.); (C.P.); (A.M.)
| | | | - Roberta Lotti
- DermoLab, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (M.Q.); (E.P.); (C.P.); (A.M.)
| | - Elisabetta Palazzo
- DermoLab, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (M.Q.); (E.P.); (C.P.); (A.M.)
| | - Letizia Campanini
- DermoLab, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (M.Q.); (E.P.); (C.P.); (A.M.)
| | | | - Gaëlle Bellemere
- Expanscience Laboratoires, 28230 Eprernon, France; (C.B.); (G.B.)
| | - Carlo Pincelli
- DermoLab, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (M.Q.); (E.P.); (C.P.); (A.M.)
| | - Alessandra Marconi
- DermoLab, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (M.Q.); (E.P.); (C.P.); (A.M.)
| |
Collapse
|
|
13
|
Cuyler M, Twilley D, Thipe VC, Mandiwana V, Kalombo ML, Ray SS, Rikhotso-Mbungela RS, Janse van Vuuren A, Coetsee W, Katti KV, Lall N. Antihistamine and Wound Healing Potential of Gold Nanoparticles Synthesized Using Bulbine frutescens (L.) Willd. Nanotechnol Sci Appl 2024; 17:59-76. [PMID: 38504832 PMCID: PMC10949377 DOI: 10.2147/nsa.s445116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 02/22/2024] [Indexed: 03/21/2024] Open
Abstract
Background Atopic dermatitis (eczema) is an inflammatory skin condition with synthetic treatments that induce adverse effects and are ineffective. One of the proposed causes for the development of the condition is the outside-in hypothesis, which states that eczema is caused by a disruption in the skin barrier. These disruptions include developing dry cracked skin, which promotes the production of histamine. Bulbine frutescens (BF) is traditionally used to treat wounds and eczema; however, limited research has been conducted to scientifically validate this. Furthermore, gold nanoparticles (AuNPs) have been used to repair damaged skin; however, no research has been conducted on AuNPs synthesized using BF. Purpose The study aimed to determine whether BF alleviated skin damage through wound healing, reducing the production of histamine and investigate whether AuNPs synthesized using BF would enhance biological activity. Methods Four extracts and four synthesized AuNPs were prepared using BF and their antiproliferative and wound healing properties against human keratinocyte cells (HaCaT) were evaluated. Thereafter, the selected samples antiproliferative activity and antihistamine activity against phorbol 12-myristate 13-acetate (PMA) stimulated granulocytes were evaluated. Results Of the eight samples, the freeze-dried leaf juice (BFE; p < 0.01) extract and its AuNPs (BFEAuNPs; p < 0.05) displayed significant wound closure at 100 µg/mL and were further evaluated. The selected samples displayed a fifty percent inhibitory concentration (IC50) of >200 µg/mL against PMA stimulated granulocytes. Compared to the untreated (media with PMA) control (0.30 ± 0.02 ng/mL), BFEAuNPs significantly inhibited histamine production at a concentration of 100 (p < 0.01) and 50 µg/mL (p < 0.001). Conclusion BFE and BFEAuNPs stimulated wound closure, while BFEAuNPs significantly inhibited histamine production. Further investigation into BFEAuNPs in vivo wound healing activity and whether it can target histamine-associated receptors on mast cells as a potential mechanism of action should be considered.
Collapse
Affiliation(s)
- Marizé Cuyler
- Department of Plant and Soil Sciences, University of Pretoria, Pretoria, Gauteng, 0002, South Africa
| | - Danielle Twilley
- Department of Plant and Soil Sciences, University of Pretoria, Pretoria, Gauteng, 0002, South Africa
| | - Velaphi C Thipe
- Department of Radiology, Institute of Green Nanotechnology, University of Missouri, Columbia, MO, 65212, USA
| | - Vusani Mandiwana
- Chemical Cluster Centre for Nanostructures and Advanced Materials, Council for Scientific and Industrial Research, Pretoria, 0001, South Africa
| | - Michel L Kalombo
- Chemical Cluster Centre for Nanostructures and Advanced Materials, Council for Scientific and Industrial Research, Pretoria, 0001, South Africa
| | - Suprakas S Ray
- DST/CSIR National Centre for Nanostructured Materials, Council for Scientific and Industrial Research, Pretoria, 0001, South Africa
| | | | - Arno Janse van Vuuren
- Centre for High Transmission Electron Microscopy, Nelson Mandela University, Port Elizabeth, 6031, South Africa
| | - Will Coetsee
- Botanica Natural Products Pty (Ltd), Canterbury Farm MR 254, Alldays, Limpopo, 0909, South Africa
| | - Kattesh V Katti
- Department of Radiology, Institute of Green Nanotechnology, University of Missouri, Columbia, MO, 65212, USA
| | - Namrita Lall
- Department of Plant and Soil Sciences, University of Pretoria, Pretoria, Gauteng, 0002, South Africa
- School of Natural Resources, University of Missouri, Columbia, MO, 65211, USA
- College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, 570015, India
- Bio-Tech Research and Development Institute, University of the West Indies 770, Kingston, Jamaica
| |
Collapse
|
|
14
|
Ribatti D. Mast cells are at the interface between the external environment and the inner organism. Front Med (Lausanne) 2024; 10:1332047. [PMID: 38239615 PMCID: PMC10794488 DOI: 10.3389/fmed.2023.1332047] [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: 11/02/2023] [Accepted: 11/30/2023] [Indexed: 01/22/2024] Open
Abstract
Mast cells localized at the level of the mucosal barrier in the skin, lung, and gastrointestinal tract, intervene in the modulation of the function of the epithelial cells and are involved in innate and adaptive defensive responses. In this context, mast cells intervene in the recognition and clearance of microbial pathogens. This mini-review article discusses the role of mast cells in these barrier systems.
Collapse
Affiliation(s)
- Domenico Ribatti
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, Bari, Italy
| |
Collapse
|
|
15
|
Qiao W, Xie T, Lu J, Jia T, Kaku K. Identification of potential hub genes associated with atopic dermatitis-like recombinant human epidermal model using integrated transcriptomic and proteomic analysis. BIOMOLECULES & BIOMEDICINE 2024; 24:89-100. [PMID: 37540585 PMCID: PMC10787623 DOI: 10.17305/bb.2023.9439] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 07/19/2023] [Accepted: 07/19/2023] [Indexed: 08/06/2023]
Abstract
Atopic dermatitis (AD) is a severe inflammatory skin disorder, characterized by elevated levels of proinflammatory cytokines that fuel a vicious cycle of inflammation. While inflammatory recombinant human epidermal (RHE) models relevant to AD have been established, comprehensive understanding remains limited. To illuminate changes and identify potential hub genes involved in AD-related inflammation, RHE models, stimulated by an inflammatory cocktail including polyinosinic-polycytidylic acid, tumor necrosis factor alpha (TNF-α), interleukin 4 (IL-4) and interleukin 13 (IL-13), were constructed and examined using tandem mass tags-proteomic coupled with RNA-seq transcriptomic analyses. Principal component analysis (PCA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functional enrichment were employed for the analysis of related genes and proteins. Protein-protein interaction networks helped identify hub genes, which were further confirmed by qPCR and western blot. We observed high expression of thymic stromal lymphopoietin in the inflammatory RHE. Our study identified 2369 differentially expressed genes and 880 differentially expressed proteins in the cocktail-induced group versus the normal control group. A total of 248 overlapping symbols were enriched in various biological processes and signaling pathways, including cornification envelope, cell-cell junction, calcium ion binding, extracellular matrix receptor, terpenoid backbone biosynthesis, and peroxisome proliferator-activated receptors signaling pathway, among others. Among the 248 overlapping symbols, CytoHubba identified 10 hub molecules, namely signal transducer and activator of transcription 3 (STAT3), integrin subunit beta 1 (ITGB1), filaggrin (FLG), involucrin (IVL), DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 (DDX58), small proline rich protein 1B (SPRR1B), interferon induced with helicase C domain 1 (IFIH1), desmoglein 1 (DSG1), collagen type XVII alpha 1 chain (COL17A1), and integrin subunit alpha 6 (ITGA6), based on the degree. These integrated results offer valuable insights into the molecular mechanisms of AD and present potential tools for screening cosmetic formulations intended for the treatment of AD.
Collapse
Affiliation(s)
- Wu Qiao
- Pigeon Manufacturing Shanghai CO., LTD., Shanghai, China
| | - Tong Xie
- Pigeon Manufacturing Shanghai CO., LTD., Shanghai, China
| | - Jing Lu
- Pigeon Manufacturing Shanghai CO., LTD., Shanghai, China
| | - Tinghan Jia
- Pigeon Manufacturing Shanghai CO., LTD., Shanghai, China
| | - Ken Kaku
- Pigeon Manufacturing Shanghai CO., LTD., Shanghai, China
| |
Collapse
|
|
16
|
Park HY, Kweon DK, Kim JK. Upregulation of tight junction-related proteins by hyaluronic acid in human HaCaT keratinocytes. BIOACTIVE CARBOHYDRATES AND DIETARY FIBRE 2023; 30:100374. [DOI: 10.1016/j.bcdf.2023.100374] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
17
|
Hatano Y, Elias PM. "Outside-to-inside," "inside-to-outside," and "intrinsic" endogenous pathogenic mechanisms in atopic dermatitis: keratinocytes as the key functional cells involved in both permeability barrier dysfunction and immunological alterations. Front Immunol 2023; 14:1239251. [PMID: 37638035 PMCID: PMC10451066 DOI: 10.3389/fimmu.2023.1239251] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 07/31/2023] [Indexed: 08/29/2023] Open
Abstract
Permeability barrier disruption has been shown to induce immunological alterations (i.e., an "outside-to-inside" pathogenic mechanism). Conversely, several inflammatory and immunological mechanisms reportedly interrupt permeability barrier homeostasis (i.e., an "inside-to-outside" pathogenic mechanism). It is now widely recognized that alterations of even a single molecule in keratinocytes can lead to not only permeability barrier dysfunction but also to immunological alterations. Such a simultaneous, bidirectional functional change by keratinocytes is herein named an "intrinsic" pathogenic mechanism. Molecules and/or pathways involved in this mechanism could be important not only as factors in disease pathogenesis but also as potential therapeutic targets for inflammatory cutaneous diseases, such as atopic dermatitis, psoriasis, and prurigo nodularis. Elevation of skin surface pH following permeability barrier abrogation comprises one of the key pathogenic phenomena of the "outside-to-inside" mechanism. Not only type 2 cytokines (e.g., IL-4, IL-13, IL-31) but also type 1 (e.g. IFN-γ), and type 3 (e.g., IL-17, IL-22) as well as several other inflammatory factors (e.g. histamine) can disrupt permeability barrier homeostasis and are all considered part of the "inside-to-outside" mechanism. Finally, examples of molecules relevant to the "intrinsic" pathogenic mechanism include keratin 1, filaggrin, and peroxisome proliferator-activated receptor-α (PPARα).
Collapse
Affiliation(s)
- Yutaka Hatano
- Department of Dermatology, Faculty of Medicine, Oita University, Oita, Japan
| | - Peter M. Elias
- Department of Dermatology, University of California, San Francisco and Veterans Affairs Health Care System, San Francisco, CA, United States
| |
Collapse
|
|
18
|
Mihele DM, Nistor PA, Bruma G, Mitran CI, Mitran MI, Condrat CE, Tovaru M, Tampa M, Georgescu SR. Mast Cell Activation Syndrome Update-A Dermatological Perspective. J Pers Med 2023; 13:1116. [PMID: 37511729 PMCID: PMC10381535 DOI: 10.3390/jpm13071116] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/26/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
Mast cells (MCs) are infamous for their role in potentially fatal anaphylaxis reactions. In the last two decades, a more complex picture has emerged, as it has become obvious that MCs are much more than just IgE effectors of anaphylaxis. MCs are defenders against a host of infectious and toxic aggressions (their interactions with other components of the immune system are not yet fully understood) and after the insult has ended, MCs continue to play a role in inflammation regulation and tissue repair. Unfortunately, MC involvement in pathology is also significant. Apart from their role in allergies, MCs can proliferate clonally to produce systemic mastocytosis. They have also been implicated in excessive fibrosis, keloid scaring, graft rejection and chronic inflammation, especially at the level of the skin and gut. In recent years, the term MC activation syndrome (MCAS) was proposed to account for symptoms caused by MC activation, and clear diagnostic criteria have been defined. However, not all authors agree with these criteria, as some find them too restrictive, potentially leaving much of the MC-related pathology unaccounted for. Here, we review the current knowledge on the physiological and pathological roles of MCs, with a dermatological emphasis, and discuss the MCAS classification.
Collapse
Affiliation(s)
- Dana Mihaela Mihele
- Dermatology Department, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
- Dermatology Department, Victor Babes Clinical Hospital of Infectious and Tropical Diseases, 030303 Bucharest, Romania
| | - Paul Andrei Nistor
- Internal Medicine Department, Emergency University Hospital Bucharest, 169 Independence Blvd, 050098 Bucharest, Romania
| | - Gabriela Bruma
- Dermatology Department, Victor Babes Clinical Hospital of Infectious and Tropical Diseases, 030303 Bucharest, Romania
| | - Cristina Iulia Mitran
- Microbiology Department, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
| | - Madalina Irina Mitran
- Microbiology Department, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
| | - Carmen Elena Condrat
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania
- Department of Obstetrics and Gynecology, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
| | - Mihaela Tovaru
- Dermatology Department, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
- Dermatology Department, Victor Babes Clinical Hospital of Infectious and Tropical Diseases, 030303 Bucharest, Romania
| | - Mircea Tampa
- Dermatology Department, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
- Dermatology Department, Victor Babes Clinical Hospital of Infectious and Tropical Diseases, 030303 Bucharest, Romania
| | - Simona Roxana Georgescu
- Dermatology Department, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
- Dermatology Department, Victor Babes Clinical Hospital of Infectious and Tropical Diseases, 030303 Bucharest, Romania
| |
Collapse
|
|
19
|
Riedl R, Wallert M, Lorkowski S, Wiegand C. Effects of Histamine and the α-Tocopherol Metabolite α-13'-COOH in an Atopic Dermatitis Full-Thickness Skin Model. MOLECULES (BASEL, SWITZERLAND) 2023; 28:molecules28010440. [PMID: 36615633 PMCID: PMC9824170 DOI: 10.3390/molecules28010440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/28/2022] [Accepted: 12/30/2022] [Indexed: 01/06/2023]
Abstract
Atopic dermatitis is a T-cell mediated inflammatory skin disease with detected elevated levels of histamine in skin or plasma. In this study, the effects of histamine in a TH2 cytokine environment on human keratinocytes and three-dimensional skin models were investigated. These models were used to explore the anti-inflammatory properties of the α-tocopherol-derived long-chain metabolite α-13'-carboxychromanol (α-13'-COOH). Histamine and TH2 cytokine-induced proliferation of keratinocytes was studied using a scratch assay. The inflammatory marker interleukin-8 was significantly increased in healthy and TH2 cytokine-stimulated keratinocytes and skin models after histamine treatment. The incubation of full-thickness skin models with TH2 cytokines and histamine resulted in morphological changes in the epidermal layer, interpreted as hyperkeratosis. α-13'-COOH significantly decreased interleukin-8 in these disease-associated skin models. Histological staining of filaggrin showed skin-strengthening effects following α-13'-COOH treatment, without changes in mRNA expression. Cytokeratin 10 mRNA expression tended to be increased in response to α-13'-COOH. Anti-allergic properties of α-13'-COOH were studied by pre-incubation of human leukocytes with α-13'-COOH. This resulted in reduced sulfido-leukotriene synthesis. The hyperproliferation effect of histamine in atopic dermatitis skin models may be of further interest to the study of disease-associated morphological changes. Moreover, α-13'-COOH is a promising natural compound for the treatment of inflammatory skin diseases.
Collapse
Affiliation(s)
- Rebecca Riedl
- Department of Dermatology, University Hospital Jena, 07743 Jena, Germany
- Institute of Nutritional Science, Friedrich Schiller University Jena, 07743 Jena, Germany
- Correspondence:
| | - Maria Wallert
- Institute of Nutritional Science, Friedrich Schiller University Jena, 07743 Jena, Germany
- Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig, 07743 Jena, Germany
| | - Stefan Lorkowski
- Institute of Nutritional Science, Friedrich Schiller University Jena, 07743 Jena, Germany
- Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig, 07743 Jena, Germany
| | - Cornelia Wiegand
- Department of Dermatology, University Hospital Jena, 07743 Jena, Germany
| |
Collapse
|
|
20
|
Analysis of clinical presentations, lip transepidermal water loss and associated dermatological conditions in patients with chronic cheilitis. Sci Rep 2022; 12:22497. [PMID: 36577807 PMCID: PMC9797544 DOI: 10.1038/s41598-022-27115-9] [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: 05/31/2022] [Accepted: 12/26/2022] [Indexed: 12/29/2022] Open
Abstract
Chronic cheilitis (CC) is a spectrum of inflammatory changes of unknown etiology that affect the vermilion of the lips. This study aimed to describe the epidemiology, clinical presentations and risk factors of CC. Patients with CC were recruited from the National Clinical Research Center for Oral Disease of China. A convenience sample of inhabitants who live in the same geographical region were recruited as the control group. The lip skin transepidermal water loss (TEWL) and capacitance of CC patients were compared with that of age- and gender-matched controls. Our results demonstrated that of the 109 patients with CC, 72 (66.1%; 95% CI: 57.0-75.1%) were female. The common clinical presentations of CC consisted of desquamation (n = 99; 90.8%), and/or chapping (n = 81; 74.3%), and/or pruritus (n = 64; 58.7%). Multivariable analysis showed that allergic dermatologic diseases (P < 0.001; OR: 4.5; 95% CI: 2.4-8.4), anemia (P = 0.001; OR: 3.3; 95% CI: 1.5-7.5), and indoor/outdoor alternate working environment (P < 0.001; OR: 2.1; 95% CI: 1.5-2.8) were the significant risk factors for CC. The mean lip skin TEWL was found to be significantly higher, while the capacitance was lower in CC patients compared to that of control individuals. This study provides insights into the etiopathogenesis of CC and may help clinicians to identify the most effective management strategies.
Collapse
|
|
21
|
Fujikawa M, Sugimoto H, Tamura R, Fujikawa K, Yamagishi A, Ueda Y. Effects of mucopolysaccharide polysulphate on tight junction barrier in human epidermal keratinocytes. Exp Dermatol 2022; 31:1676-1684. [PMID: 35770317 PMCID: PMC9796026 DOI: 10.1111/exd.14637] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 06/20/2022] [Accepted: 06/27/2022] [Indexed: 12/30/2022]
Abstract
Tight junctions (TJs) play important roles in epidermal barrier function and their dysfunction is involved in the pathogenesis of various skin diseases, including atopic dermatitis (AD). Mucopolysaccharide polysulphate (MPS) is the active ingredient of a moisturizing agent used to treat xerosis in patients with AD; however, its mechanism of action on TJ barrier function remains unclear. To elucidate the effects of MPS on TJs, adult human epidermal keratinocyte (HEKa) cells were exposed to MPS, subjected to Western blotting and quantitative PCR analyses for the investigation of TJ-related factors. MPS treatment significantly increased the mRNA and protein expression of claudin-1 (CLDN1) and zonula occludens-1, and significantly increased transepithelial electrical resistance (TEER), which indicates TJ integrity. Conversely, the sulphated and non-sulphated glycosaminoglycans, chondroitin sulphate and hyaluronic acid, respectively, had little effect on TEER or the expression of mRNAs or TJ-related proteins. Interestingly, MPS treatment also inactivated the extracellular signal-regulated kinase signalling pathway, which is known to negatively regulate CLDN1 expression. Furthermore, MPS notably improved the reduction in CLDN1 expression and TEER caused by histamine, which is upregulated in the skin of patients with AD and is known to disrupt the TJ barrier function. Taken together, these findings demonstrate that treatment with the moisturizing agent, MPS, can repair TJ dysfunction and could therefore represent a new therapeutic option for treating patients with AD.
Collapse
Affiliation(s)
| | | | - Rie Tamura
- Kyoto R&D Center, Maruho Co., Ltd.KyotoJapan
| | | | | | - Yuhki Ueda
- Kyoto R&D Center, Maruho Co., Ltd.KyotoJapan
| |
Collapse
|
|
22
|
Maguire G. Chronic inflammation induced by microneedling and the use of bone marrow stem cell cytokines. J Tissue Viability 2022; 31:687-692. [DOI: 10.1016/j.jtv.2022.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 08/07/2022] [Accepted: 08/16/2022] [Indexed: 10/14/2022]
|
|
23
|
Lim JH, Kim DH, Noh KH, Jung CR, Kang HM. The proliferative and multipotent epidermal progenitor cells for human skin reconstruction in vitro and in vivo. Cell Prolif 2022; 55:e13284. [PMID: 35723171 PMCID: PMC9436902 DOI: 10.1111/cpr.13284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 05/16/2022] [Accepted: 05/23/2022] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVES The skin exhibits tremendous regenerative potential, as different types of progenitor and stem cells regulate skin homeostasis and damage. However, in vitro primary keratinocytes present with several drawbacks, such as high donor variability, short lifespan, and limited donor tissue availability. Therefore, more stable primary keratinocytes are needed to generate multiple uniform in vitro and in vivo skin models. RESULTS We identified epidermal progenitor cells from primary keratinocytes using Integrin beta 1 (ITGB1) an epidermal stem cell marker markedly decreased after senescence in vitro. Epidermal progenitor cells exhibited unlimited proliferation and the potential for multipotent differentiation capacity. Moreover, they could completely differentiate to form an organotypic skin model including conversed mesenchymal cells in the dermis and could mimic the morphologic and biochemical processes of human epidermis. We also discovered that proliferation and the multipotent differentiation capacity of these cells relied on ITGB1 expression. Eventually, we examined the in vitro and in vivo wound healing capacity of these epidermal progenitor cells. CONCLUSIONS Overall, the findings suggest that these stable and reproducible cells can differentiate into multiple lineages, including human skin models. They are a potentially powerful tool for studying skin regeneration, skin diseases, and are an alternative for in vivo experiments.
Collapse
Affiliation(s)
- Jung Hwa Lim
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Dae Hun Kim
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.,Department of Functional Genomics, Korea University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Kyung Hee Noh
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| | - Cho-Rok Jung
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.,Department of Functional Genomics, Korea University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Hyun Mi Kang
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
| |
Collapse
|
|
24
|
Beck LA, Cork MJ, Amagai M, De Benedetto A, Kabashima K, Hamilton JD, Rossi AB. Type 2 Inflammation Contributes to Skin Barrier Dysfunction in Atopic Dermatitis. JID INNOVATIONS 2022; 2:100131. [PMID: 36059592 PMCID: PMC9428921 DOI: 10.1016/j.xjidi.2022.100131] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/04/2022] [Accepted: 01/06/2022] [Indexed: 01/02/2023] Open
Abstract
Skin barrier dysfunction, a defining feature of atopic dermatitis (AD), arises from multiple interacting systems. In AD, skin inflammation is caused by host-environment interactions involving keratinocytes as well as tissue-resident immune cells such as type 2 innate lymphoid cells, basophils, mast cells, and T helper type 2 cells, which produce type 2 cytokines, including IL-4, IL-5, IL-13, and IL-31. Type 2 inflammation broadly impacts the expression of genes relevant for barrier function, such as intracellular structural proteins, extracellular lipids, and junctional proteins, and enhances Staphylococcus aureus skin colonization. Systemic anti‒type 2 inflammation therapies may improve dysfunctional skin barrier in AD.
Collapse
Key Words
- AD, atopic dermatitis
- AMP, antimicrobial peptide
- CLDN, claudin
- FFA, free fatty acid
- ILC2, type 2 innate lymphoid cell
- Jaki, Jak inhibitor
- K, keratin
- KC, keratinocyte
- MMP, matrix metalloproteinase
- NMF, natural moisturizing factor
- PAR, protease-activated receptor
- PDE-4, phosphodiesterase-4
- SC, stratum corneum
- SG, stratum granulosum
- TCI, topical calcineurin inhibitor
- TCS, topical corticosteroid
- TEWL, transepidermal water loss
- TJ, tight junction
- TLR, toll-like receptor
- TNF-α, tumor necrosis factor alpha
- TYK, tyrosine kinase
- Th, T helper
- ZO, zona occludens
- hBD, human β-defensin
Collapse
Affiliation(s)
- Lisa A. Beck
- Department of Dermatology, University of Rochester Medical Center, Rochester, New York, USA,Correspondence: Lisa A. Beck, Department of Dermatology, University of Rochester Medical Center, 601 Elmwood Ave, Box 697, Rochester, New York 14642, USA.
| | - Michael J. Cork
- Sheffield Dermatology Research, Department of Infection, Immunity and Cardiovascular Disease (IICD), The University of Sheffield, The Medical School, Sheffield, United Kingdom
| | - Masayuki Amagai
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan,Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Anna De Benedetto
- Department of Dermatology, University of Rochester Medical Center, Rochester, New York, USA
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | | |
Collapse
|
|
25
|
Barbieux C, Bonnet des Claustres M, Fahrner M, Petrova E, Tsoi LC, Gouin O, Leturcq F, Nicaise-Roland P, Bole C, Béziat V, Bourrat E, Schilling O, Gudjonsson JE, Hovnanian A. Netherton syndrome subtypes share IL-17/IL-36 signature with distinct IFN-α and allergic responses. J Allergy Clin Immunol 2022; 149:1358-1372. [PMID: 34543653 DOI: 10.1016/j.jaci.2021.08.024] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 08/12/2021] [Accepted: 08/27/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Netherton syndrome (NS) is a rare recessive skin disorder caused by loss-of-function mutations in SPINK5 encoding the protease inhibitor LEKTI (lymphoepithelial Kazal-type-related inhibitor). NS patients experience severe skin barrier defects, display inflammatory skin lesions, and have superficial scaling with atopic manifestations. They present with typical ichthyosis linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE). OBJECTIVE We used a combination of several molecular profiling methods to comprehensively characterize the skin, immune cells, and allergic phenotypes of NS-ILC and NS-SE patients. METHODS We studied a cohort of 13 patients comprising 9 NS-ILC and 4 NS-SE. RESULTS Integrated multiomics revealed abnormal epidermal proliferation and differentiation and IL-17/IL-36 signatures in lesion skin and in blood in both NS endotypes. Although the molecular profiles of NS-ILC and NS-SE lesion skin were very similar, nonlesion skin of each disease subtype displayed distinctive molecular features. Nonlesion and lesion NS-SE epidermis showed activation of the type I IFN signaling pathway, while lesion NS-ILC skin differed from nonlesion NS-ILC skin by increased complement activation and neutrophil infiltration. Serum cytokine profiling and immunophenotyping of circulating lymphocytes showed a TH2-driven allergic response in NS-ILC, whereas NS-SE patients displayed mainly a TH9 axis with increased CCL22/MDC and CCL17/TARC serum levels. CONCLUSIONS This study confirms IL-17/IL-36 as the predominant signaling axes in both NS endotypes and unveils molecular features distinguishing NS-ILC and NS-SE. These results identify new therapeutic targets and could pave the way for precision medicine of NS.
Collapse
Affiliation(s)
- Claire Barbieux
- INSERM UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France
| | | | - Matthias Fahrner
- Institute for Surgical Pathology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, Freiburg, Germany; Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany
| | - Evgeniya Petrova
- INSERM UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France
| | - Lam C Tsoi
- INSERM UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France
| | - Olivier Gouin
- INSERM UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France
| | - Florent Leturcq
- INSERM UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France
| | - Pascale Nicaise-Roland
- Department of Immunology, Bichat Hospital, AP-HP-Nord, Paris, France; INSERM UMR 1152, Paris, France
| | | | - Vivien Béziat
- INSERM UMR 1163, Laboratory of Human Genetics of Infectious Diseases, Imagine Institute, Paris, France
| | | | - Oliver Schilling
- Institute for Surgical Pathology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | | | - Alain Hovnanian
- University of Paris, Paris, France; Department of Genetics, Necker Hospital for Sick Children (AP-HP), Paris, France; Department of Dermatology, University of Michigan, Ann Arbor, Mich.
| |
Collapse
|
|
26
|
Szöllősi AG, Oláh A, Lisztes E, Griger Z, Tóth BI. Pruritus: A Sensory Symptom Generated in Cutaneous Immuno-Neuronal Crosstalk. Front Pharmacol 2022; 13:745658. [PMID: 35321329 PMCID: PMC8937025 DOI: 10.3389/fphar.2022.745658] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 02/07/2022] [Indexed: 12/21/2022] Open
Abstract
Pruritus or itch generated in the skin is one of the most widespread symptoms associated with various dermatological and systemic (immunological) conditions. Although many details about the molecular mechanisms of the development of both acute and chronic itch were uncovered in the last 2 decades, our understanding is still incomplete and the clinical management of pruritic conditions is one of the biggest challenges in daily dermatological practice. Recent research revealed molecular interactions between pruriceptive sensory neurons and surrounding cutaneous cell types including keratinocytes, as well as resident and transient cells of innate and adaptive immunity. Especially in inflammatory conditions, these cutaneous cells can produce various mediators, which can contribute to the excitation of pruriceptive sensory fibers resulting in itch sensation. There also exists significant communication in the opposite direction: sensory neurons can release mediators that maintain an inflamed, pruritic tissue-environment. In this review, we summarize the current knowledge about the sensory transduction of pruritus detailing the local intercellular interactions that generate itch. We especially emphasize the role of various pruritic mediators in the bidirectional crosstalk between cutaneous non-neuronal cells and sensory fibers. We also list various dermatoses and immunological conditions associated with itch, and discuss the potential immune-neuronal interactions promoting the development of pruritus in the particular diseases. These data may unveil putative new targets for antipruritic pharmacological interventions.
Collapse
Affiliation(s)
- Attila Gábor Szöllősi
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Attila Oláh
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Erika Lisztes
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zoltán Griger
- Division of Clinical Immunology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Balázs István Tóth
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- *Correspondence: Balázs István Tóth,
| |
Collapse
|
|
27
|
Kordulewska N, Topa J, Cieślińska A, Jarmołowska B. Osthole Regulates Secretion of Pro-Inflammatory Cytokines and Expression of TLR2 and NF-κB in Normal Human Keratinocytes and Fibroblasts. J Inflamm Res 2022; 15:1501-1519. [PMID: 35261546 PMCID: PMC8898189 DOI: 10.2147/jir.s349216] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 01/20/2022] [Indexed: 12/13/2022] Open
Affiliation(s)
- Natalia Kordulewska
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury, Olsztyn, Poland
- Correspondence: Natalia Kordulewska, Tel + 48 89 523 37 63, Fax + 48 89 535 20 15, Email
| | - Justyna Topa
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdańsk, Gdańsk, Poland
| | - Anna Cieślińska
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury, Olsztyn, Poland
| | - Beata Jarmołowska
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury, Olsztyn, Poland
| |
Collapse
|
|
28
|
Kim DY, Won KJ, Hwang DI, Kim NY, Kim B, Lee HM. 1-Iodohexadecane Alleviates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis in Mice: Possible Involvements of the Skin Barrier and Mast Cell SNARE Proteins. Molecules 2022; 27:1560. [PMID: 35268661 PMCID: PMC8911872 DOI: 10.3390/molecules27051560] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/24/2022] [Accepted: 02/24/2022] [Indexed: 11/27/2022] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory dermal disease with symptoms that include inflammation, itching, and dry skin. 1-Iodohexadecane is known as a component of Chrysanthemum boreale essential oil that has an inhibitory effect on AD-like lesions. However, its effects on AD-related pathological events have not been investigated. Here, we explored the effects of 1-iodohexadecane on AD lesion-related in vitro and in vivo responses and the mechanism involved using human keratinocytes (HaCaT cells), mast cells (RBL-2H3 cells), and a 2,4-dinitrochlorobenzene (DNCB)-induced mouse model (male BALB/c) of AD. Protein analyses were performed by immunoblotting or immunohistochemistry. In RBL-2H3 cells, 1-iodohexadecane inhibited immunoglobulin E-induced releases of histamine and β-hexosaminidase and the expression of VAMP8 protein (vesicle-associated membrane proteins 8; a soluble N-ethylmaleimide-sensitive factor attachment protein receptor [SNARE] protein). In HaCaT cells, 1-iodohexadecane enhanced filaggrin and loricrin expressions; in DNCB-treated mice, it improved AD-like skin lesions, reduced epidermal thickness, mast cell infiltration, and increased filaggrin and loricrin expressions (skin barrier proteins). In addition, 1-iodohexadecane reduced the β-hexosaminidase level in the serum of DNCB-applied mice. These results suggest that 1-iodohexadecane may ameliorate AD lesion severity by disrupting SNARE protein-linked degranulation and/or by enhancing the expressions of skin barrier-related proteins, and that 1-iodohexadecane has therapeutic potential for the treatment of AD.
Collapse
Affiliation(s)
- Do Yoon Kim
- Division of Cosmetic and Biotechnology, College of Life and Health Sciences, Hoseo University, Asan 31499, Korea; (D.Y.K.); (D.I.H.); (N.Y.K.)
| | - Kyung-Jong Won
- Department of Physiology and Medical Science, School of Medicine, Konkuk University, Seoul 05029, Korea; (K.-J.W.); (B.K.)
| | - Dae Il Hwang
- Division of Cosmetic and Biotechnology, College of Life and Health Sciences, Hoseo University, Asan 31499, Korea; (D.Y.K.); (D.I.H.); (N.Y.K.)
| | - Nan Young Kim
- Division of Cosmetic and Biotechnology, College of Life and Health Sciences, Hoseo University, Asan 31499, Korea; (D.Y.K.); (D.I.H.); (N.Y.K.)
| | - Bokyung Kim
- Department of Physiology and Medical Science, School of Medicine, Konkuk University, Seoul 05029, Korea; (K.-J.W.); (B.K.)
| | - Hwan Myung Lee
- Division of Cosmetic and Biotechnology, College of Life and Health Sciences, Hoseo University, Asan 31499, Korea; (D.Y.K.); (D.I.H.); (N.Y.K.)
| |
Collapse
|
|
29
|
Usuki S, Tamura N, Tamura T, Yuyama K, Mikami D, Mukai K, Igarashi Y. Konjac Ceramide (kCer)-Mediated Signal Transduction of the Sema3A Pathway Promotes HaCaT Keratinocyte Differentiation. BIOLOGY 2022; 11:biology11010121. [PMID: 35053118 PMCID: PMC8772740 DOI: 10.3390/biology11010121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/07/2022] [Accepted: 01/08/2022] [Indexed: 11/16/2022]
Abstract
Simple Summary Konjac ceramide (kCer) is a unique molecular species of plant-type ceramide, and is a potential Sema3A-like ligand of Nrp1. kCer suppresses histamine-stimulated cell migration of HaCaT keratinocytes. This effect of kCer is not due to histamine-activated GPCRs, but rather to Sema3A-Nrp1 receptor binding. The present study focused on the ability of kCer to induce cell differentiation, in addition to its anti-migratory effects. We demonstrated that the effects of kCer on cell migration and cell differentiation are perpetuated by a cascade of crosstalk between pathways downstream of Nrp1 and GPCR in HaCaT cells. Abstract Histamines suppress epidermal keratinocyte differentiation. Previously, we reported that konjac ceramide (kCer) suppresses histamine-stimulated cell migration of HaCaT keratinocytes. kCer specifically binds to Nrp1 and does not interact with histamine receptors. The signaling mechanism of kCer in HaCaT cells is also controlled by an intracellular signaling cascade activated by the Sema3A-Nrp1 pathway. In the present study, we demonstrated that kCer treatment induced HaCaT keratinocyte differentiation after migration of immature cells. kCer-induced HaCaT cell differentiation was accompanied by some features of keratinocyte differentiation markers. kCer induced activating phosphorylation of p38MAPK and c-Fos, which increased the protein levels of involucrin that was the latter differentiation marker. In addition, we demonstrated that the effects of both kCer and histamines are regulated by an intracellular mechanism of Rac1 activation/RhoA inhibition downstream of the Sema3A/Nrp1 receptor and histamine/GPCR pathways. In summary, the effects of kCer on cell migration and cell differentiation are regulated by cascade crosstalk between downstream Nrp1 and histamine-GPCR pathways in HaCaT cells.
Collapse
Affiliation(s)
- Seigo Usuki
- Lipid Biofunction Section, Frontier Research Center for Advanced Material and Life Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan; (K.Y.); (D.M.); (K.M.); (Y.I.)
- Correspondence: ; Tel.: +81-11-706-9086; Fax: +81-11-706-9024
| | - Noriko Tamura
- National Institute of Advanced Industrial Science and Technology (AIST), Sapporo 062-8517, Japan; (N.T.); (T.T.)
| | - Tomohiro Tamura
- National Institute of Advanced Industrial Science and Technology (AIST), Sapporo 062-8517, Japan; (N.T.); (T.T.)
| | - Kohei Yuyama
- Lipid Biofunction Section, Frontier Research Center for Advanced Material and Life Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan; (K.Y.); (D.M.); (K.M.); (Y.I.)
| | - Daisuke Mikami
- Lipid Biofunction Section, Frontier Research Center for Advanced Material and Life Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan; (K.Y.); (D.M.); (K.M.); (Y.I.)
| | - Katsuyuki Mukai
- Lipid Biofunction Section, Frontier Research Center for Advanced Material and Life Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan; (K.Y.); (D.M.); (K.M.); (Y.I.)
- R & D Headquarters, Daicel Corporation, Tokyo 108-8230, Japan
| | - Yasuyuki Igarashi
- Lipid Biofunction Section, Frontier Research Center for Advanced Material and Life Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan; (K.Y.); (D.M.); (K.M.); (Y.I.)
| |
Collapse
|
|
30
|
Kakade P, Wairkar S, Lohakare S, Shah P, Patravale V. Probiotics for Atopic Dermatitis: An Update. PROBIOTIC RESEARCH IN THERAPEUTICS 2022:197-244. [DOI: 10.1007/978-981-16-5628-6_9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
31
|
Vorstandlechner V, Laggner M, Copic D, Klas K, Direder M, Chen Y, Golabi B, Haslik W, Radtke C, Tschachler E, Hötzenecker K, Ankersmit HJ, Mildner M. The serine proteases dipeptidyl-peptidase 4 and urokinase are key molecules in human and mouse scar formation. Nat Commun 2021; 12:6242. [PMID: 34716325 PMCID: PMC8556235 DOI: 10.1038/s41467-021-26495-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 10/08/2021] [Indexed: 01/23/2023] Open
Abstract
Despite recent advances in understanding skin scarring, mechanisms triggering hypertrophic scar formation are still poorly understood. In the present study, we investigate mature human hypertrophic scars and developing scars in mice at single cell resolution. Compared to normal skin, we find significant differences in gene expression in most cell types present in scar tissue. Fibroblasts show the most prominent alterations in gene expression, displaying a distinct fibrotic signature. By comparing genes upregulated in murine fibroblasts during scar development with genes highly expressed in mature human hypertrophic scars, we identify a group of serine proteases, tentatively involved in scar formation. Two of them, dipeptidyl-peptidase 4 (DPP4) and urokinase (PLAU), are further analyzed in functional assays, revealing a role in TGFβ1-mediated myofibroblast differentiation and over-production of components of the extracellular matrix in vitro. Topical treatment with inhibitors of DPP4 and PLAU during scar formation in vivo shows anti-fibrotic activity and improvement of scar quality, most prominently after application of the PLAU inhibitor BC-11. In this study, we delineate the genetic landscape of hypertrophic scars and present insights into mechanisms involved in hypertrophic scar formation. Our data suggest the use of serine protease inhibitors for the treatment of skin fibrosis.
Collapse
Affiliation(s)
- Vera Vorstandlechner
- Laboratory for Cardiac and Thoracic Diagnosis, Regeneration and Applied Immunology, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
- Aposcience AG (FN 308089y), Dresdner Straße 87/A21, Vienna, Austria
- Department of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria
| | - Maria Laggner
- Laboratory for Cardiac and Thoracic Diagnosis, Regeneration and Applied Immunology, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
- Aposcience AG (FN 308089y), Dresdner Straße 87/A21, Vienna, Austria
| | - Dragan Copic
- Laboratory for Cardiac and Thoracic Diagnosis, Regeneration and Applied Immunology, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
- Aposcience AG (FN 308089y), Dresdner Straße 87/A21, Vienna, Austria
| | - Katharina Klas
- Laboratory for Cardiac and Thoracic Diagnosis, Regeneration and Applied Immunology, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
- Aposcience AG (FN 308089y), Dresdner Straße 87/A21, Vienna, Austria
| | - Martin Direder
- Laboratory for Cardiac and Thoracic Diagnosis, Regeneration and Applied Immunology, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
- Aposcience AG (FN 308089y), Dresdner Straße 87/A21, Vienna, Austria
| | - Yiyan Chen
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
- University of Applied Sciences, FH Campus Wien, Vienna, Austria
| | - Bahar Golabi
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Werner Haslik
- Department of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria
| | - Christine Radtke
- Department of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria
| | - Erwin Tschachler
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Konrad Hötzenecker
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Hendrik Jan Ankersmit
- Laboratory for Cardiac and Thoracic Diagnosis, Regeneration and Applied Immunology, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.
- Aposcience AG (FN 308089y), Dresdner Straße 87/A21, Vienna, Austria.
| | - Michael Mildner
- Department of Dermatology, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
32
|
Lu Y, Chen H, Zhang J, Tang B, Zhang H, Ma C, Tang X, Li L, Wu J, Wei J, Li S, Yang L, Han L, Lu C. Fuzhenghefuzhiyang Formula (FZHFZY) Improves Epidermal Differentiation via Suppression of the Akt/mTORC1/S6K1 Signalling Pathway in Psoriatic Models. Front Pharmacol 2021; 12:650816. [PMID: 34456715 PMCID: PMC8386017 DOI: 10.3389/fphar.2021.650816] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/22/2021] [Indexed: 12/13/2022] Open
Abstract
Psoriasis is a chronic proliferative skin disorder characterised by abnormal epidermal differentiation. The Fuzhenghefuzhiyang (FZHFZY) formula created by Chuanjian Lu, a master of Chinese medicine in dermatology, has been external used in the Guangdong Provincial Hospital of Chinese Medicine for the treatment of psoriasis, but its mechanisms of action against psoriasis remain poorly understood. This study involved an exploration of the effects of FZHFZY on epidermal differentiation and its underlying mechanisms in interleukin (IL)-17A/IL-22/interferon (IFN)-γ/tumour necrosis factor (TNF)-α–stimulated HaCaT cells and in a mouse model of imiquimod (IMQ)-induced psoriasis. Cell viability was assessed by MTT assay. Epidermal differentiation was detected by reverse-transcription polymerase chain reaction and western blotting. Histological evaluation of the skin tissue was performed via haematoxylin and eosin staining, and the Akt/mTORC1/S6K1 pathway was analysed by western blotting. FZHFZY inhibited proliferation and improved epidermal differentiation in IL-17A/IL-22/IFN-γ/TNF-α–induced HaCaT cells. FZHFZY ameliorated symptoms of psoriasis, regulated epidermal differentiation and inhibited phosphorylation of the Akt/mTORC1/S6K1 pathway in the skin of mice with imiquimod-induced psoriasis. Our results suggest that FZHFZY may exhibit therapeutic action against psoriasis by regulating epidermal differentiation via inhibition of the Akt/mTORC1/S6K1 pathway.
Collapse
Affiliation(s)
- Yue Lu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.,Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China.,Guangdong Provincial Clinical Medicine Research Center for Chinese Medicine Dermatology, Guangzhou, China.,Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Haiming Chen
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.,Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China.,Guangdong Provincial Clinical Medicine Research Center for Chinese Medicine Dermatology, Guangzhou, China.,Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Junhong Zhang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.,Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bin Tang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.,Guangdong Provincial Clinical Medicine Research Center for Chinese Medicine Dermatology, Guangzhou, China.,Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hongyu Zhang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.,Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Changju Ma
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.,Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaojuan Tang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.,Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Li Li
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.,Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jingjing Wu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.,Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jianan Wei
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.,Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China.,Guangdong Provincial Clinical Medicine Research Center for Chinese Medicine Dermatology, Guangzhou, China.,Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shaoping Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, China
| | - Lei Yang
- Guangzhou Youcare Biopharmaceutics Co., Ltd, Guangzhou, China
| | - Ling Han
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.,Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China.,Guangdong Provincial Clinical Medicine Research Center for Chinese Medicine Dermatology, Guangzhou, China.,Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chuanjian Lu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.,Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China.,Guangdong Provincial Clinical Medicine Research Center for Chinese Medicine Dermatology, Guangzhou, China.,Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, China
| |
Collapse
|
|
33
|
Mitamura Y, Ogulur I, Pat Y, Rinaldi AO, Ardicli O, Cevhertas L, Brüggen MC, Traidl-Hoffmann C, Akdis M, Akdis CA. Dysregulation of the epithelial barrier by environmental and other exogenous factors. Contact Dermatitis 2021; 85:615-626. [PMID: 34420214 PMCID: PMC9293165 DOI: 10.1111/cod.13959] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/11/2021] [Accepted: 08/18/2021] [Indexed: 12/26/2022]
Abstract
The “epithelial barrier hypothesis” proposes that the exposure to various epithelial barrier–damaging agents linked to industrialization and urbanization underlies the increase in allergic diseases. The epithelial barrier constitutes the first line of physical, chemical, and immunological defense against environmental factors. Recent reports have shown that industrial products disrupt the epithelial barriers. Innate and adaptive immune responses play an important role in epithelial barrier damage. In addition, recent studies suggest that epithelial barrier dysfunction plays an essential role in the pathogenesis of the atopic march by allergen sensitization through the transcutaneous route. It is evident that external factors interact with the immune system, triggering a cascade of complex reactions that damage the epithelial barrier. Epigenetic and microbiome changes modulate the integrity of the epithelial barrier. Robust and simple measurements of the skin barrier dysfunction at the point‐of‐care are of significant value as a biomarker, as recently reported using electrical impedance spectroscopy to directly measure barrier defects. Understanding epithelial barrier dysfunction and its mechanism is key to developing novel strategies for the prevention and treatment of allergic diseases. The aim of this review is to summarize recent studies on the pathophysiological mechanisms triggered by environmental factors that contribute to the dysregulation of epithelial barrier function.
Collapse
Affiliation(s)
- Yasutaka Mitamura
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos
| | - Ismail Ogulur
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos.,Division of Pediatric Allergy and Immunology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Yagiz Pat
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos.,Department of Medical Microbiology, Faculty of Medicine, Aydin Menderes University, Aydin, Turkey
| | - Arturo O Rinaldi
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos
| | - Ozge Ardicli
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos.,Department of Microbiology, Faculty of Veterinary Medicine, Bursa Uludag University, Bursa, Turkey
| | - Lacin Cevhertas
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos.,Department of Medical Immunology, Institute of Health Sciences, Bursa Uludag University, Bursa, Turkey
| | - Marie-Charlotte Brüggen
- Christine Kühne-Center for Allergy Research and Education, Davos.,Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Claudia Traidl-Hoffmann
- Christine Kühne-Center for Allergy Research and Education, Davos.,Department of Environmental Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Mubeccel Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos
| | - Cezmi A Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos.,Christine Kühne-Center for Allergy Research and Education, Davos
| |
Collapse
|
|
34
|
Yang CC, Hung YL, Li HJ, Lin YF, Wang SJ, Chang DC, Pu CM, Hung CF. Quercetin inhibits histamine-induced calcium influx in human keratinocyte via histamine H4 receptors. Int Immunopharmacol 2021; 96:107620. [PMID: 33862555 DOI: 10.1016/j.intimp.2021.107620] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 03/18/2021] [Accepted: 03/25/2021] [Indexed: 11/16/2022]
Abstract
Histamine is released from mast cells when tissues are inflamed or stimulated by allergens. Activation of histamine receptors and calcium influx via TRPV1 could be related to histamine-induced itch and skin inflammation. Quercetin is known to have anti-inflammatory and anti-itching effects. This study aims to understand whether quercetin can directly affect histamine-induced calcium influx in human keratinocyte. In it, we investigated quercetin, which acts on histamine-induced intracellular free calcium ([Ca2+]i) elevation in human keratinocyte. Changes in [Ca2+]i were measured using spectrofluorometry and confocal Imaging. We detected the expression of IL-8 after treatment of quercetin using qRT-PCR and evaluated its anti-itching effect in BALB/c mice. We also performed a docking study to estimate the binding affinity of quercetin to H4 receptors. We found that quercetin pretreatment decreased histamine-induced [Ca2+]i elevation in a concentration-dependent manner. The inhibitory effect of quercetin on histamine-induced [Ca2+]i elevation was blocked by JNJ7777120, a selective H4 antagonist, as well as by U73122, a PLC inhibitor, and by GF109203X, a PKC inhibitor. We also found that H4 agonist (4-methylhistamine)-induced [Ca2+]i elevation could be inhibited by quercetin. Moreover, the selective TRPV1 blocker capsazepine significantly suppressed the quercetin-mediated inhibition of histamine-induced [Ca2+]i elevation, whereas the TRPV4 blocker GSK2193874 had no effect. Last, quercetin decreased histamine and H4 agonist-induced IL-8 expression in keratinocyte and inhibited the scratching behavior-induced compound 48/80 in BALB/c mice. The molecular docking study also showed that quercetin exhibited high binding affinities with H4 receptors (autodock scores for H4 = -8.7 kcal/mol). These data suggest that quercetin could decrease histamine 4 receptor-induced calcium influx through the TRPV1 channel and could provide a molecular mechanism of quercetin in anti-itching, anti-inflammatory, and unpleasant sensations.
Collapse
Affiliation(s)
- Chung-Chi Yang
- Division of Cardiovascular Medicine, Taoyuan Armed Forces General Hospital, Taoyuan City, Taiwan.
| | - Yen-Ling Hung
- Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan.
| | - Hsin-Ju Li
- Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan.
| | - Ya-Fan Lin
- Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Su-Jane Wang
- School of Medicine, Fu Jen Catholic University, Xinzhuang, New Taipei City, Taiwan.
| | - Der-Chen Chang
- Department of Mathematics and Statistics and Department of Computer Science, Georgetown University, Washington, DC 20057, USA.
| | - Chi-Ming Pu
- School of Medicine, Fu Jen Catholic University, Xinzhuang, New Taipei City, Taiwan; Division of Plastic Surgery, Department of Surgery, Cathay General Hospital, Taipei 10630, Taiwan.
| | - Chi-Feng Hung
- Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan; Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Medicine, Fu Jen Catholic University, Xinzhuang, New Taipei City, Taiwan; Program in Pharmaceutical Biotechnology, Fu Jen Catholic University, New Taipei City, Taiwan.
| |
Collapse
|
|
35
|
Lachner J, Derdak S, Mlitz V, Wagner T, Holthaus KB, Ehrlich F, Mildner M, Tschachler E, Eckhart L. An In Vitro Model of Avian Skin Reveals Evolutionarily Conserved Transcriptional Regulation of Epidermal Barrier Formation. J Invest Dermatol 2021; 141:2829-2837. [PMID: 34116064 DOI: 10.1016/j.jid.2021.04.029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 03/29/2021] [Accepted: 04/12/2021] [Indexed: 01/23/2023]
Abstract
The function of the skin as a barrier against a dry environment evolved in a common ancestor of terrestrial vertebrates such as mammals and birds. However, it is unknown which elements of the genetic program of skin barrier formation are evolutionarily ancient and conserved. In this study, we determined the transcriptomes of chicken keratinocytes (KCs) grown in monolayer culture and in an organotypic model of avian skin. The differentiation-associated changes in global gene expression were compared with previously published transcriptome changes of human KCs cultured under equivalent conditions. We found that specific keratins and genes of the epidermal differentiation complex were upregulated during the differentiation of both chicken and human KCs. Likewise, the transcriptional upregulation of genes that control the synthesis and transport of lipids, anti-inflammatory cytokines of the IL-1 family, protease inhibitors, and other regulators of tissue homeostasis was conserved in the KCs of both species. However, some avian KC differentiation-associated transcripts lack homologs in mammals and vice versa, indicating a genetic basis for taxon-specific skin features. The results of this study reveal an evolutionarily ancient program in which dynamic gene transcription controls the metabolism and transport of lipids as well as other core processes during terrestrial skin barrier formation.
Collapse
Affiliation(s)
- Julia Lachner
- Skin Biology Laboratory, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Sophia Derdak
- Core Facilities, Medical University of Vienna, Vienna, Austria
| | - Veronika Mlitz
- Skin Biology Laboratory, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Tanja Wagner
- Skin Biology Laboratory, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Karin Brigit Holthaus
- Skin Biology Laboratory, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Florian Ehrlich
- Skin Biology Laboratory, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Michael Mildner
- Skin Biology Laboratory, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Erwin Tschachler
- Skin Biology Laboratory, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Leopold Eckhart
- Skin Biology Laboratory, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
36
|
Voss M, Kotrba J, Gaffal E, Katsoulis-Dimitriou K, Dudeck A. Mast Cells in the Skin: Defenders of Integrity or Offenders in Inflammation? Int J Mol Sci 2021; 22:ijms22094589. [PMID: 33925601 PMCID: PMC8123885 DOI: 10.3390/ijms22094589] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/23/2021] [Accepted: 04/25/2021] [Indexed: 12/13/2022] Open
Abstract
Mast cells (MCs) are best-known as key effector cells of immediate-type allergic reactions that may even culminate in life-threatening anaphylactic shock syndromes. However, strategically positioned at the host–environment interfaces and equipped with a plethora of receptors, MCs also play an important role in the first-line defense against pathogens. Their main characteristic, the huge amount of preformed proinflammatory mediators embedded in secretory granules, allows for a rapid response and initiation of further immune effector cell recruitment. The same mechanism, however, may account for detrimental overshooting responses. MCs are not only detrimental in MC-driven diseases but also responsible for disease exacerbation in other inflammatory disorders. Focusing on the skin as the largest immune organ, we herein review both beneficial and detrimental functions of skin MCs, from skin barrier integrity via host defense mechanisms to MC-driven inflammatory skin disorders. Moreover, we emphasize the importance of IgE-independent pathways of MC activation and their role in sustained chronic skin inflammation and disease exacerbation.
Collapse
Affiliation(s)
- Martin Voss
- Medical Faculty, Institute for Molecular and Clinical Immunology, Otto-Von-Guericke-University Magdeburg, 39120 Magdeburg, Germany; (M.V.); (J.K.); (K.K.-D.)
| | - Johanna Kotrba
- Medical Faculty, Institute for Molecular and Clinical Immunology, Otto-Von-Guericke-University Magdeburg, 39120 Magdeburg, Germany; (M.V.); (J.K.); (K.K.-D.)
| | - Evelyn Gaffal
- Laboratory for Experimental Dermatology, Department of Dermatology, University Hospital Magdeburg, 39120 Magdeburg, Germany;
| | - Konstantinos Katsoulis-Dimitriou
- Medical Faculty, Institute for Molecular and Clinical Immunology, Otto-Von-Guericke-University Magdeburg, 39120 Magdeburg, Germany; (M.V.); (J.K.); (K.K.-D.)
| | - Anne Dudeck
- Medical Faculty, Institute for Molecular and Clinical Immunology, Otto-Von-Guericke-University Magdeburg, 39120 Magdeburg, Germany; (M.V.); (J.K.); (K.K.-D.)
- Health Campus Immunology, Infectiology and Inflammation, Otto-Von-Guericke-University Magdeburg, 39120 Magdeburg, Germany
- Correspondence:
| |
Collapse
|
|
37
|
Meloni M, Balzaretti S, Collard N, Desaint S, Laperdrix C. Reproducing the scalp microbiota community: co-colonization of a 3D reconstructed human epidermis with C. acnes and M. restricta. Int J Cosmet Sci 2021; 43:235-245. [PMID: 33469935 DOI: 10.1111/ics.12688] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 12/10/2020] [Accepted: 12/18/2020] [Indexed: 12/14/2022]
Abstract
OBJECTIVE A 3D reconstructed human epidermis (RHE) model colonized with specific microbial strains was developed to model the complex interactions between strains of the human scalp hair. METHODS Reconstructed human epidermis was colonized with Cutibacterium acnes and Malassezia restricta for 72 h. The epidermal model was characterized in terms of morphology, using immune-labelling targeting biomarkers for barrier structure, proliferation, differentiation and anti-microbial defence. The barrier function was assessed by transepithelial electrical eesistance (TEER) measurements. In order to study the microorganisms on the epidermal model, viable counts and phenotype ultrastructure analysis were performed by scanning electron microscopy (SEM). RESULTS The RHE colonized with C. acnes did not lead to severe modifications of the physiological barrier integrity and viability, though it shows aggregates. M. restricta formed large aggregates by a close interaction with the RHE, thus causing both a strong decrease in barrier function and structure degradation and an increased human beta defensin 2 (HBD2) expression. The co-colonized model resulted in barrier depletion, but the overall damage was less severe, respecting the single colonization with M. restricta. The developed 'scalp model' allowed to identify morphological modifications leading to uncontrolled epidermal renewal. CONCLUSION This study shows a pre-clinical model that recapitulates the interactions that can occur between site-specific microbial strains and keratinocytes in dandruff condition. The model can be applied to assess ingredients and products' mechanism of action.
Collapse
|
|
38
|
Chieosilapatham P, Kiatsurayanon C, Umehara Y, Trujillo-Paez JV, Peng G, Yue H, Nguyen LTH, Niyonsaba F. Keratinocytes: innate immune cells in atopic dermatitis. Clin Exp Immunol 2021; 204:296-309. [PMID: 33460469 DOI: 10.1111/cei.13575] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 12/29/2020] [Accepted: 01/04/2021] [Indexed: 02/06/2023] Open
Abstract
The skin is a unique immune organ that constitutes a complex network of physical, chemical and microbiological barriers against external insults. Keratinocytes are the most abundant cell type in the epidermis. These cells form the physical skin barrier and represent the first line of the host defense system by sensing pathogens via innate immune receptors, initiating anti-microbial responses and producing various cytokines, chemokines and anti-microbial peptides, which are important events in immunity. A damaged epidermal barrier in atopic dermatitis allows the penetration of potential allergens and pathogens to activate keratinocytes. Among the dysregulation of immune responses in atopic dermatitis, activated keratinocytes play a role in several biological processes that contribute to the pathogenesis of atopic dermatitis. In this review, we summarize the current understanding of the innate immune functions of keratinocytes in the pathogenesis of atopic dermatitis, with a special emphasis on skin-derived anti-microbial peptides and atopic dermatitis-related cytokines and chemokines in keratinocytes. An improved understanding of the innate immunity mediated by keratinocytes can provide helpful insight into the pathophysiological processes of atopic dermatitis and support new therapeutic efforts.
Collapse
Affiliation(s)
- P Chieosilapatham
- Division of Immunology, Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - C Kiatsurayanon
- Institute of Dermatology, Department of Medical Services, Ministry of Public Health, Bangkok, Thailand
| | - Y Umehara
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - J V Trujillo-Paez
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - G Peng
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - H Yue
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - L T H Nguyen
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - F Niyonsaba
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Faculty of International Liberal Arts, Juntendo University, Tokyo, Japan
| |
Collapse
|
|
39
|
Vu YH, Hashimoto-Hachiya A, Takemura M, Yumine A, Mitamura Y, Nakahara T, Furue M, Tsuji G. IL-24 Negatively Regulates Keratinocyte Differentiation Induced by Tapinarof, an Aryl Hydrocarbon Receptor Modulator: Implication in the Treatment of Atopic Dermatitis. Int J Mol Sci 2020; 21:ijms21249412. [PMID: 33321923 PMCID: PMC7764126 DOI: 10.3390/ijms21249412] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 11/30/2020] [Accepted: 12/09/2020] [Indexed: 12/15/2022] Open
Abstract
Skin barrier dysfunction, including reduced filaggrin (FLG) and loricrin (LOR) expression, plays a critical role in atopic dermatitis (AD) development. Since aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates keratinocyte differentiation, it is a potential target for AD treatment. Recently, clinical studies have shown that tapinarof, an AHR modulator, attenuated the development of AD. To examine the molecular mechanism involved in this, we analyzed tapinarof-treated normal human epidermal keratinocytes (NHEKs). Tapinarof upregulated FLG and LOR mRNA and protein expression in an AHR-dependent manner. Tapinarof also induced the secretion of IL-24, a cytokine that activates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), leading to the downregulation of FLG and LOR expression. Knockdown of either IL-24 or STAT3 expression by small interfering RNA (siRNA) transfection augmented the upregulation of FLG and LOR expression induced by tapinarof, suggesting that inhibition of the IL-24/STAT3 axis during AHR activation supports the improvement of skin barrier dysfunction. Furthermore, tapinarof alone could restore the downregulation of FLG and LOR expression induced by IL-4, a key cytokine of AD, and its combination with JAK inhibitors enhanced this effect. These findings provide a new strategy for treating AD using AHR modulators and JAK inhibitors.
Collapse
Affiliation(s)
- Yen Hai Vu
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan; (Y.H.V.); (A.H.-H.); (M.T.); (A.Y.); (Y.M.); (T.N.); (M.F.)
| | - Akiko Hashimoto-Hachiya
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan; (Y.H.V.); (A.H.-H.); (M.T.); (A.Y.); (Y.M.); (T.N.); (M.F.)
| | - Masaki Takemura
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan; (Y.H.V.); (A.H.-H.); (M.T.); (A.Y.); (Y.M.); (T.N.); (M.F.)
| | - Ayako Yumine
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan; (Y.H.V.); (A.H.-H.); (M.T.); (A.Y.); (Y.M.); (T.N.); (M.F.)
| | - Yasutaka Mitamura
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan; (Y.H.V.); (A.H.-H.); (M.T.); (A.Y.); (Y.M.); (T.N.); (M.F.)
| | - Takeshi Nakahara
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan; (Y.H.V.); (A.H.-H.); (M.T.); (A.Y.); (Y.M.); (T.N.); (M.F.)
- Division of Skin Surface Sensing, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan
| | - Masutaka Furue
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan; (Y.H.V.); (A.H.-H.); (M.T.); (A.Y.); (Y.M.); (T.N.); (M.F.)
- Division of Skin Surface Sensing, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan
- Research and Clinical Center for Yusho and Dioxin, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan
| | - Gaku Tsuji
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan; (Y.H.V.); (A.H.-H.); (M.T.); (A.Y.); (Y.M.); (T.N.); (M.F.)
- Research and Clinical Center for Yusho and Dioxin, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan
- Correspondence: ; Tel.: +81-92-642-5585; Fax: +81-92-642-5600
| |
Collapse
|
|
40
|
Haftek M, McAleer MA, Jakasa I, McLean WI, Kezic S, Irvine AD. Changes in nano-mechanical properties of human epidermal cornified cells in children with atopic dermatitis. Wellcome Open Res 2020; 5:97. [PMID: 32954014 DOI: 10.12688/wellcomeopenres.15729.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/17/2020] [Indexed: 01/08/2023] Open
Abstract
Background: Impaired skin barrier is an important etiological factor in atopic dermatitis (AD). The structural protein filaggrin (FLG) plays a major role in maintenance of the competent skin barrier and its deficiency is associated with enhanced susceptibility to mechanical injury. Here we examined biomechanical characteristics of the corneocytes in children with AD and healthy controls. Methods: We recruited 20 children with AD and 7 healthy children. They were genotyped for filaggrin gene ( FLG) loss-of-function mutations. Stratum corneum was collected from clinically unaffected skin by adhesive tapes. Cell stiffness (apparent elastic modulus, Ea) was determined by atomic force microscopy and filaggrin degradation products (NMF) by liquid chromatography. Skin barrier function was assessed through trans-epidermal water loss (TEWL) and disease severity by the SCORing Atopic Dermatitis (SCORAD) tool. Results: Corneocytes collected from AD patients showed a decreased elastic modulus which was strongly correlated with NMF and TEWL, but not with SCORAD. As compared with healthy controls, AD patients had reduced TEWL and NMF levels regardless of FLG mutations. NMF was strongly correlated with TEWL. Conclusion: Our findings demonstrate that AD patients have decreased corneocyte stiffness which correlates with reduced levels of filaggrin degradation products, NMF and skin barrier function. Altered mechanical properties of the corneocytes likely contribute to the loss of mechanical integrity of the SC and to reduced skin barrier function in AD.
Collapse
Affiliation(s)
- Marek Haftek
- Laboratory of Tissue Biology and Therapeutic Engineering, CNRS UMR5305, Lyon, France
| | - Maeve A McAleer
- Dermatology, Children's Health Ireland at Crumlin, Dublin, Ireland.,National Children's Research Centre, Dublin, Ireland
| | - Ivone Jakasa
- Laboratory for Analytical Chemistry, Dept. of Chemistry and Biochemistry,, University of Zagreb, Zagreb, Croatia
| | - Wh Irwin McLean
- Dermatology and Genetic Medicine, Univsersity of Dundee, Dundee, UK
| | - Sanja Kezic
- Coronel Institute of Occupational Health, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Alan D Irvine
- Dermatology, Children's Health Ireland at Crumlin, Dublin, Ireland.,National Children's Research Centre, Dublin, Ireland.,Clinical Medicine, Trinity College Dublin, Dublin, Ireland
| |
Collapse
|
|
41
|
Genetic and Epigenetic Aspects of Atopic Dermatitis. Int J Mol Sci 2020; 21:ijms21186484. [PMID: 32899887 PMCID: PMC7554821 DOI: 10.3390/ijms21186484] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/02/2020] [Accepted: 09/02/2020] [Indexed: 12/21/2022] Open
Abstract
Atopic dermatitis is a heterogeneous disease, in which the pathogenesis is associated with mutations in genes encoding epidermal structural proteins, barrier enzymes, and their inhibitors; the role of genes regulating innate and adaptive immune responses and environmental factors inducing the disease is also noted. Recent studies point to the key role of epigenetic changes in the development of the disease. Epigenetic modifications are mainly mediated by DNA methylation, histone acetylation, and the action of specific non-coding RNAs. It has been documented that the profile of epigenetic changes in patients with atopic dermatitis (AD) differs from that observed in healthy people. This applies to the genes affecting the regulation of immune response and inflammatory processes, e.g., both affecting Th1 bias and promoting Th2 responses and the genes of innate immunity, as well as those encoding the structural proteins of the epidermis. Understanding of the epigenetic alterations is therefore pivotal to both create new molecular classifications of atopic dermatitis and to enable the development of personalized treatment strategies.
Collapse
|
|
42
|
Lestienne F, Viodé C, Ceruti I, Carrere S, Bessou-Touya S, Duplan H, Castex-Rizzi N. Cutaneous sensitivity modulation by Aquaphilus dolomiae extract-G3 on in vitro models of neuro-inflammation. J Eur Acad Dermatol Venereol 2020; 34 Suppl 5:43-48. [PMID: 32870552 DOI: 10.1111/jdv.16641] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 05/07/2020] [Accepted: 05/11/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Inflammatory skin disorders, including atopic dermatitis (AD), associated pruritus and sensitive skin, have a complex multifactorial pathogenesis including neurogenic inflammation involving the release in blood and skin of neurotransmitters such as substance P (SP). AIMS AND METHODS In vitro models evaluated the effect of the original biological extract of Aquaphilus dolomiae extract-G3 (ADE-G3) on cutaneous neurogenic inflammation. RESULTS ADE-G3 significantly inhibited SP-stimulated release of IL-1β and TNF-α from normal human epidermal keratinocytes; significantly and dose-dependently inhibited SP-stimulated activation of human mast cells; significantly inhibited veratridine-stimulated release of SP from human sensory neurons; modulated expression of genes involved in lipid synthesis, innate immunity, corneocyte scaffolding and epidermal differentiation in a histamine-sensitized reconstructed human epidermis model; and, when applied topically to ex vivo human explants, inhibited IL-8 and histamine release. CONCLUSIONS Topically applied ADE-G3, once formulated, may improve neuro-inflammation in patients with inflammatory skin disorders.
Collapse
Affiliation(s)
- F Lestienne
- Department of Pharmacology, Pierre Fabre Dermo-Cosmétique, Toulouse Cedex 1, France
| | - C Viodé
- Department of Pharmacology, Pierre Fabre Dermo-Cosmétique, Toulouse Cedex 1, France
| | - I Ceruti
- Department of Pharmacology, Pierre Fabre Dermo-Cosmétique, Toulouse Cedex 1, France
| | - S Carrere
- Department of Pharmacology, Pierre Fabre Dermo-Cosmétique, Toulouse Cedex 1, France
| | - S Bessou-Touya
- Department of Pharmacology, Pierre Fabre Dermo-Cosmétique, Toulouse Cedex 1, France
| | - H Duplan
- Department of Pharmacology, Pierre Fabre Dermo-Cosmétique, Toulouse Cedex 1, France
| | - N Castex-Rizzi
- Department of Pharmacology, Pierre Fabre Dermo-Cosmétique, Toulouse Cedex 1, France
| |
Collapse
|
|
43
|
Brough HA, Nadeau KC, Sindher SB, Alkotob SS, Chan S, Bahnson HT, Leung DYM, Lack G. Epicutaneous sensitization in the development of food allergy: What is the evidence and how can this be prevented? Allergy 2020; 75:2185-2205. [PMID: 32249942 PMCID: PMC7494573 DOI: 10.1111/all.14304] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/26/2020] [Accepted: 03/28/2020] [Indexed: 12/14/2022]
Abstract
There is increasing evidence regarding the importance of allergic sensitization through the skin. In this review, we provide an overview of the atopic march and immune mechanism underlying the sensitization and effector phase of food allergy. We present experimental models and human data that support the concept of epicutaneous sensitization and how this forms one half of the dual-allergen exposure hypothesis. We discuss specific important elements in the skin (FLG and other skin barrier gene mutations, Langerhans cells, type 2 innate lymphoid cells, IL-33, TSLP) that have important roles in the development of allergic responses as well as the body of evidence on environmental allergen exposure and how this can sensitize an individual. Given the link between skin barrier impairment, atopic dermatitis, food allergy, allergic asthma, and allergic rhinitis, it is logical that restoring the skin barrier and prevention or treating atopic dermatitis would have beneficial effects on prevention of related allergic diseases, particularly food allergy. We present the experimental and human studies that have evaluated this approach and discuss various factors which may influence the success of these approaches, such as the type of emollient chosen for the intervention, the role of managing skin inflammation, and differences between primary and secondary prevention of atopic dermatitis to achieve the desired outcome.
Collapse
Affiliation(s)
- Helen A Brough
- Paediatric Allergy Group, Department of Women and Children's Health, School of Life Course Sciences, King's College London, St. Thomas' Hospital, London, UK
- Paediatric Allergy Group, Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, Guys' Hospital, London, UK
- Children's Allergy Service, Evelina Children's Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK
| | - Kari C Nadeau
- Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Allergy, Immunology and Rheumatology, Stanford University, Stanford, CA, USA
| | - Sayantani B Sindher
- Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA, USA
| | - Shifaa S Alkotob
- Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA, USA
| | - Susan Chan
- Paediatric Allergy Group, Department of Women and Children's Health, School of Life Course Sciences, King's College London, St. Thomas' Hospital, London, UK
- Paediatric Allergy Group, Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, Guys' Hospital, London, UK
- Children's Allergy Service, Evelina Children's Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK
| | - Henry T Bahnson
- Benaroya Research Institute and Immune Tolerance Network, Seattle, WA, USA
| | - Donald Y M Leung
- Department of Pediatrics, Division of Pediatric Allergy-Immunology, National Jewish Health, Denver, CO, USA
| | - Gideon Lack
- Paediatric Allergy Group, Department of Women and Children's Health, School of Life Course Sciences, King's College London, St. Thomas' Hospital, London, UK
- Paediatric Allergy Group, Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, Guys' Hospital, London, UK
- Children's Allergy Service, Evelina Children's Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK
| |
Collapse
|
|
44
|
Imaging of metabolic activity adaptations to UV stress, drugs and differentiation at cellular resolution in skin and skin equivalents - Implications for oxidative UV damage. Redox Biol 2020; 37:101583. [PMID: 32713735 PMCID: PMC7767734 DOI: 10.1016/j.redox.2020.101583] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 12/29/2022] Open
Abstract
The epidermis is a multi-layered epithelium that consists mainly of keratinocytes which proliferate in its basal layer and then differentiate to form the stratum corneum, the skin's ultimate barrier to the environment. During differentiation keratinocyte function, chemical composition, physical properties, metabolism and secretion are profoundly changed. Extrinsic or intrinsic stressors, like ultraviolet (UV) radiation thus may differently affect the epidermal keratinocytes, depending on differentiation stage. Exposure to UV elicits the DNA damage responses, activation of pathways which detoxify or repair damage or induction of programmed cell death when the damage was irreparable. Recently, rapid diversion of glucose flux into the pentose phosphate pathway (PPP) was discovered as additional mechanism by which cells rapidly generate reduction equivalents and precursors for nucleotides - both being in demand after UV damage. There is however little known about the correlation of such metabolic activity with differentiation state, cell damage and tissue localization of epidermal cells. We developed a method to correlate the activity of G6PD, the first and rate-limiting enzyme of this metabolic UV response, at cellular resolution to cell type, differentiation state, and cell damage in human skin and in organotypic reconstructed epidermis. We thereby could verify rapid activation of G6PD as an immediate UVB response not only in basal but also in differentiating epidermal keratinocytes and found increased activity in cells which initiated DNA damage responses. When keratinocytes had been UVB irradiated before organotypic culture, their distribution within the skin equivalent was abnormal and the G6PD activity was reduced compared to neighboring cells. Finally, we found that the anti-diabetic and potential anti-aging drug metformin strongly induced G6PD activity throughout reconstructed epidermis. Activation of the protective pentose phosphate pathway may be useful to enhance the skin's antioxidant defense systems and DNA damage repair capacity on demand.
Collapse
|
|
45
|
Haftek M, McAleer MA, Jakasa I, McLean WI, Kezic S, Irvine AD. Changes in nano-mechanical properties of human epidermal cornified cells in children with atopic dermatitis. Wellcome Open Res 2020; 5:97. [PMID: 32954014 PMCID: PMC7477645 DOI: 10.12688/wellcomeopenres.15729.2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/14/2020] [Indexed: 01/24/2023] Open
Abstract
Background: Impaired skin barrier is an important etiological factor in atopic dermatitis (AD). The structural protein filaggrin (FLG) plays a major role in maintenance of the competent skin barrier and its deficiency is associated with enhanced susceptibility to mechanical injury. Here we examined biomechanical characteristics of the corneocytes in children with AD and healthy controls. Methods: We recruited 20 children with AD and 7 healthy children. They were genotyped for filaggrin gene ( FLG) loss-of-function mutations. Stratum corneum was collected from clinically unaffected skin by adhesive tapes. Cell stiffness (apparent elastic modulus, Ea) was determined by atomic force microscopy and filaggrin degradation products (NMF) by liquid chromatography. Skin barrier function was assessed through trans-epidermal water loss (TEWL) and disease severity by the SCORing Atopic Dermatitis (SCORAD) tool. Results: Corneocytes collected from AD patients showed a decreased elastic modulus which was strongly correlated with NMF and TEWL, but not with SCORAD. As compared with healthy controls, AD patients had reduced TEWL and NMF levels regardless of FLG mutations. NMF was strongly correlated with TEWL. Conclusion: Our findings demonstrate that AD patients have decreased corneocyte stiffness which correlates with reduced levels of filaggrin degradation products, NMF and skin barrier function. Altered mechanical properties of the corneocytes likely contribute to the loss of mechanical integrity of the SC and to reduced skin barrier function in AD.
Collapse
Affiliation(s)
- Marek Haftek
- Laboratory of Tissue Biology and Therapeutic Engineering, CNRS UMR5305, Lyon, France
| | - Maeve A McAleer
- Dermatology, Children's Health Ireland at Crumlin, Dublin, Ireland.,National Children's Research Centre, Dublin, Ireland
| | - Ivone Jakasa
- Laboratory for Analytical Chemistry, Dept. of Chemistry and Biochemistry,, University of Zagreb, Zagreb, Croatia
| | - Wh Irwin McLean
- Dermatology and Genetic Medicine, Univsersity of Dundee, Dundee, UK
| | - Sanja Kezic
- Coronel Institute of Occupational Health, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Alan D Irvine
- Dermatology, Children's Health Ireland at Crumlin, Dublin, Ireland.,National Children's Research Centre, Dublin, Ireland.,Clinical Medicine, Trinity College Dublin, Dublin, Ireland
| |
Collapse
|
|
46
|
Milligan DA, Tyler EJ, Bishop CL. Tissue engineering to better understand senescence: Organotypics come of age. Mech Ageing Dev 2020; 190:111261. [PMID: 32461142 PMCID: PMC7493709 DOI: 10.1016/j.mad.2020.111261] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 05/04/2020] [Accepted: 05/08/2020] [Indexed: 12/01/2022]
Abstract
The recent advent of 'organs in a dish' has revolutionised the research landscape. These 3D culture systems have paved the way for translational, post genomics research by enabling scientists to model diseases in the laboratory, grow patient-derived organoids, and unite this technology with other cutting-edge methodologies such as drug discovery. Fields such as dermatology and neuroscience have revolutionised the development of robust 3D models, which faithfully recapitulate native physiology in vivo to provide important functional and mechanistic insights. These models have underpinned a rapid growth in the number of organs and myriad of human diseases that can be modelled in 3D, which currently includes breast, cerebral cortex, heart, intestine, kidney, liver, lung, neural tube, pancreas, prostate, skin and stomach, as well as patient derived tumours. However, so far, they have not yet been employed extensively in the study of fundamental cellular programmes such as senescence. Thus, tissue engineering and 3D culture offer an exciting opportunity to further understand the bright and dark sides of senescence in a more complex and physiologically relevant environment. Below, we will discuss previous approaches to investigating senescence and ageing using organotypic models, and some potential opportunities for future research.
Collapse
Affiliation(s)
- Deborah A Milligan
- Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK
| | - Eleanor J Tyler
- Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK
| | - Cleo L Bishop
- Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK.
| |
Collapse
|
|
47
|
Sugita K, Soyka MB, Wawrzyniak P, Rinaldi AO, Mitamura Y, Akdis M, Akdis CA. Outside-in hypothesis revisited: The role of microbial, epithelial, and immune interactions. Ann Allergy Asthma Immunol 2020; 125:517-527. [PMID: 32454094 DOI: 10.1016/j.anai.2020.05.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/14/2020] [Accepted: 05/17/2020] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Our understanding of the origin of allergic diseases has increased in recent years, highlighting the importance of microbial dysbiosis and epithelial barrier dysfunction in affected tissues. Exploring the microbial-epithelial-immune crosstalk underlying the mechanisms of allergic diseases will allow the development of novel prevention and treatment strategies for allergic diseases. DATA SOURCES This review summarizes the recent advances in microbial, epithelial, and immune interactions in atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, and asthma. STUDY SELECTIONS We performed a literature search, identifying relevant recent primary articles and review articles. RESULTS Dynamic crosstalk between the environmental factors and microbial, epithelial, and immune cells in the development of atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, and asthma underlies the pathogenesis of these diseases. There is substantial evidence in the literature suggesting that environmental factors directly affect barrier function of the epithelium. In addition, T-helper 2 (TH2) cells, type 2 innate lymphoid cells, and their cytokine interleukin 13 (IL-13) damage skin and lung barriers. The effects of environmental factors may at least in part be mediated by epigenetic mechanisms. Histone deacetylase activation by type 2 immune response has a major effect on leaky barriers and blocking of histone deacetylase activity corrects the defective barrier in human air-liquid interface cultures and mouse models of allergic asthma with rhinitis. We also present and discuss a novel device to detect and monitor skin barrier dysfunction, which provides an opportunity to rapidly and robustly assess disease severity. CONCLUSION A complex interplay between environmental factors, epithelium, and the immune system is involved in the development of systemic allergic diseases.
Collapse
Affiliation(s)
- Kazunari Sugita
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland; Division of Dermatology, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, Tottori University, Yonago, Japan.
| | - Michael B Soyka
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Department of Otorhinolaryngology, Head and Neck Surgery, University and University Hospital of Zurich, Zurich, Switzerland
| | - Paulina Wawrzyniak
- Division of Clinical Chemistry and Biochemistry and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Arturo O Rinaldi
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Yasutaka Mitamura
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland
| | - Mübeccel Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Cezmi A Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland
| |
Collapse
|
|
48
|
Leonardo TR, Shi J, Chen D, Trivedi HM, Chen L. Differential Expression and Function of Bicellular Tight Junctions in Skin and Oral Wound Healing. Int J Mol Sci 2020; 21:ijms21082966. [PMID: 32340108 PMCID: PMC7216202 DOI: 10.3390/ijms21082966] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 04/17/2020] [Accepted: 04/19/2020] [Indexed: 01/20/2023] Open
Abstract
Bicellular tight junctions are multiprotein complexes that are required for maintenance of barrier function and fence function in epithelial tissues. Wound healing in the oral cavity leads to minimal scar formation compared to the skin, and the precise mechanisms for this regenerative response remain to be elucidated. We hypothesized that oral and skin tissues express a different tight junction repertoire both at baseline and during the wound healing response, and that these molecules may be critical to the differential repair between the two tissues. We re-analyzed a mouse skin and palate epithelium microarray dataset to identify the tight junction repertoire of these tissue types. We then re-analyzed a skin and tongue wound healing microarray dataset to see how expression levels of tight junction genes change over time in response to injury. We performed in vitro scratch assays on human oral and skin keratinocyte cell lines to assay for tight junction expression over time, tight junction expression in response to lipopolysaccharide and histamine treatment, and the effects of siRNA knockdown of claudin 1 or occludin on migration and proliferation. Our data showed that oral and skin epithelium expressed different tight junction genes at baseline and during the wound healing response. Knockdown of claudin 1 or occludin led to changes in proliferation and migration in human skin keratinocytes but not oral keratinocytes. Furthermore, we also showed that skin keratinocytes were more permeable than oral keratinocytes upon histamine treatment. In conclusion, this study highlights a specific subset of functional tight junction genes that are differentially expressed between the oral and skin tissues, which may contribute to the mechanisms leading to distinct healing phenotypes in response to injury in the two tissues.
Collapse
Affiliation(s)
- Trevor R. Leonardo
- Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA;
- Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA;
| | - Junhe Shi
- Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA;
| | - Dandan Chen
- Colgate-Palmolive Company, Piscataway, NJ 08854, USA; (D.C.); (H.M.T.)
| | - Harsh M. Trivedi
- Colgate-Palmolive Company, Piscataway, NJ 08854, USA; (D.C.); (H.M.T.)
| | - Lin Chen
- Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA;
- Correspondence: ; Tel.: +1-312-413-5387; Fax: +1-312-996-0943
| |
Collapse
|
|
49
|
Schaper‐Gerhardt K, Rossbach K, Nikolouli E, Werfel T, Gutzmer R, Mommert S. The role of the histamine H 4 receptor in atopic dermatitis and psoriasis. Br J Pharmacol 2020; 177:490-502. [PMID: 30460986 PMCID: PMC7012951 DOI: 10.1111/bph.14550] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 10/22/2018] [Accepted: 10/28/2018] [Indexed: 12/13/2022] Open
Abstract
Atopic dermatitis (AD) and psoriasis are common skin diseases with a high negative impact on patients' quality of life. Both diseases are mediated by a pro-inflammatory infiltrate consisting of several cell types, such as T-cells, antigen-presenting cells and granulocytes and display disturbed keratinocyte differentiation. Given the fact that histamine levels are also highly elevated in inflamed skin, it is likely that histamine plays a relevant role in disease pathology. However, antagonists blocking histamine H1 receptor or H2 receptors are largely ineffective in reducing chronic symptoms in AD and psoriasis. Over the last years, much research has been undertaken to shed light into the mode of action of the most recently discovered histamine H4 receptor. This research has shown that H4 receptor antagonists display antipruritic and anti-inflammatory effects not only in mouse models but also in first human clinical trials, and therefore, H4 receptors might present a novel therapeutic target. In this review, we summarize the effects of the H4 receptors on different cell types, mouse models and clinical studies in regard to AD and psoriasis respectively. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.
Collapse
Affiliation(s)
- Katrin Schaper‐Gerhardt
- Division of Immunodermatology and Allergy Research, Department of Dermatology and AllergyHannover Medical SchoolHannoverGermany
| | - Kristine Rossbach
- Department of Pharmacology, Toxicology and PharmacyVeterinary School HannoverHannoverGermany
| | - Eirini Nikolouli
- Division of Immunodermatology and Allergy Research, Department of Dermatology and AllergyHannover Medical SchoolHannoverGermany
| | - Thomas Werfel
- Division of Immunodermatology and Allergy Research, Department of Dermatology and AllergyHannover Medical SchoolHannoverGermany
| | - Ralf Gutzmer
- Division of Immunodermatology and Allergy Research, Department of Dermatology and AllergyHannover Medical SchoolHannoverGermany
| | - Susanne Mommert
- Division of Immunodermatology and Allergy Research, Department of Dermatology and AllergyHannover Medical SchoolHannoverGermany
| |
Collapse
|
|
50
|
Vorstandlechner V, Laggner M, Kalinina P, Haslik W, Radtke C, Shaw L, Lichtenberger BM, Tschachler E, Ankersmit HJ, Mildner M. Deciphering the functional heterogeneity of skin fibroblasts using single-cell RNA sequencing. FASEB J 2020; 34:3677-3692. [PMID: 31930613 DOI: 10.1096/fj.201902001rr] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 12/16/2019] [Accepted: 12/16/2019] [Indexed: 02/06/2023]
Abstract
Though skin fibroblasts (FB) are the main cell population within the dermis, the different skin FB subsets are not well characterized and the traditional classification into reticular and papillary FBs has little functional relevance. To fill the gap of knowledge on FB diversity in human skin, we performed single-cell RNA sequencing. Investigation of marker genes for the different skin cell subtypes revealed a heterogeneous picture of FBs. When mapping reticular and papillary FB markers, we could not detect cluster specificity, suggesting that these two populations show a higher transcriptional heterogeneity than expected. This finding was further confirmed by in situ hybridization, showing that DPP4 was expressed in both dermal layers. Our analysis identified six FB clusters with distinct transcriptional signatures. Importantly, we could demonstrate that in human skin DPP4+ FBs are the main producers of factors involved in extracellular matrix (ECM) assembly. In conclusion, we provide evidence that hitherto considered FB markers are not ideal to characterize skin FB subpopulations in single-cell sequencing analyses. The identification of DPP4+ FBs as the main ECM-producing cells in human skin will foster the development of anti-fibrotic treatments for the skin and other organs.
Collapse
Affiliation(s)
| | - Maria Laggner
- Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Polina Kalinina
- Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Werner Haslik
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Christine Radtke
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Lisa Shaw
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Beate Maria Lichtenberger
- Skin and Endothelium Research Division, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Erwin Tschachler
- Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | | | - Michael Mildner
- Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria
| |
Collapse
|