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1
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Richardson KC, Jung K, Matsubara JA, Choy JC, Granville DJ. Granzyme B in aging and age-related pathologies. Trends Mol Med 2024; 30:1165-1179. [PMID: 39181801 DOI: 10.1016/j.molmed.2024.07.010] [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: 05/16/2024] [Revised: 07/19/2024] [Accepted: 07/24/2024] [Indexed: 08/27/2024]
Abstract
Aging is a major risk factor for pathologies that manifest later in life. Much attention is devoted towards elucidating how prolonged environmental exposures and inflammation promote biological (accelerated) tissue aging. Granzymes, a family of serine proteases, are increasingly recognized for their emerging roles in biological aging and disease. Widely recognized as intracellular mediators of cell death, granzymes, particularly granzyme B (GzmB), also accumulate in the extracellular milieu of tissues with age, contributing to chronic tissue injury, inflammation, and impaired healing. Consequently, this has prompted the field to reconsider how GzmB regulation, accumulation, and proteolysis impact health and disease with age. While GzmB is observed in numerous age-related conditions, the current review focuses on mechanistic studies where proof-of-concept has been forwarded.
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Affiliation(s)
- Katlyn C Richardson
- International Collaboration On Repair Discoveries (ICORD) Centre, Department of Pathology and Laboratory Medicine, British Columbia Professional Firefighters' Burn and Wound Healing Laboratory, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Karen Jung
- International Collaboration On Repair Discoveries (ICORD) Centre, Department of Pathology and Laboratory Medicine, British Columbia Professional Firefighters' Burn and Wound Healing Laboratory, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Joanne A Matsubara
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Jonathan C Choy
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
| | - David J Granville
- International Collaboration On Repair Discoveries (ICORD) Centre, Department of Pathology and Laboratory Medicine, British Columbia Professional Firefighters' Burn and Wound Healing Laboratory, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada; Centre for Heart Lung Innovation, Providence Research, University of British Columbia, Vancouver, BC, Canada.
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2
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Zhou L, Zhang G, Zhang K, Rao Z, Tang Z, Wang Y, Zhao J. The role of PAR2 in regulating MIF release in house dust mite-induced atopic dermatitis. Front Immunol 2024; 15:1478292. [PMID: 39416784 PMCID: PMC11479884 DOI: 10.3389/fimmu.2024.1478292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 09/16/2024] [Indexed: 10/19/2024] Open
Abstract
Atopic dermatitis (AD) is a chronic disease characterized by relapsed eczema and intractable itch, and is often triggered by house dust mites (HDM). PAR2 is a G-protein coupled receptor on keratinocytes and may be activated by HDM to affect AD processes. We first established a HDM-derived AD mouse model in wild-type (WT) and Par2-/- mice. Single cell RNA sequencing of the diseased skins found a stronger cellular communication between the ligand macrophage migration inhibitory factor (MIF) from keratinocytes and its receptors on antigen-presenting cells, suggesting the critical role of MIF in AD. HDM-WT mice showed severer skin lesions and pathological changes with stronger immunofluorescence MIF signals in skin sections than HDM-Par2-/- mice. Primary keratinocytes from WT mice stimulated with HDM or SLIGRL (PAR2 agonist) secreted more MIF in cultured medium and induced stronger immunofluorescence MIF signals than those from Par2-/- mice. The skin section of HDM-WT mice showed higher immunofluorescence signals of P115 (relating to MIF secretion) and KIF13B (possibly relating to intracellular trafficking of MIF) than that of HDM-Par2-/- mice. Acetylation of α-tubulin increased after stimulation by SLIGRL in WT keratinocytes but not in Par2-/- keratinocytes. HDM-WT mice treated with the MIF antagonist ISO-1 displayed improvement of AD-like presentations and lower expressions of IL-4, IL-13, TSLP and Arg1 (a biomarker of M2 macrophage) mRNAs. We conclude that MIF is an important cytokine and is significantly increased in the AD model. PAR2 affects AD changes by regulating the expression, intracellular trafficking, and secretion of MIF in epidermis.
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Affiliation(s)
- Lingxuan Zhou
- Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, National Clinical Research Center for Skin and Immune Disease, National Medical Products Administration (NMPA) Key Laboratory for Quality Control and Evaluation of Cosmetics, Beijing, China
| | - Guohong Zhang
- Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, National Clinical Research Center for Skin and Immune Disease, National Medical Products Administration (NMPA) Key Laboratory for Quality Control and Evaluation of Cosmetics, Beijing, China
| | - Kai Zhang
- Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, National Clinical Research Center for Skin and Immune Disease, National Medical Products Administration (NMPA) Key Laboratory for Quality Control and Evaluation of Cosmetics, Beijing, China
| | - Ziyan Rao
- Department of Biomedical Informatics, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Zhanli Tang
- Department of Dermatology, Qilu Hospital of Shandong University, Jinan, China
| | - Yang Wang
- Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, National Clinical Research Center for Skin and Immune Disease, National Medical Products Administration (NMPA) Key Laboratory for Quality Control and Evaluation of Cosmetics, Beijing, China
| | - Jiahui Zhao
- Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, National Clinical Research Center for Skin and Immune Disease, National Medical Products Administration (NMPA) Key Laboratory for Quality Control and Evaluation of Cosmetics, Beijing, China
- Chinese Institute for Brain Research (CIBR), Beijing, China
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3
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Li Y, Chen W, Zhu X, Mei H, Steinhoff M, Buddenkotte J, Wang J, Zhang W, Li Z, Dai X, Shan C, Wang J, Meng J. Neuronal BST2: A Pruritic Mediator alongside Protease-Activated Receptor 2 in the IL-27-Driven Itch Pathway. J Invest Dermatol 2024; 144:1829-1842.e4. [PMID: 38360199 DOI: 10.1016/j.jid.2024.01.025] [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: 10/29/2023] [Revised: 01/11/2024] [Accepted: 01/27/2024] [Indexed: 02/17/2024]
Abstract
Chronic itch is a common and complex symptom often associated with skin diseases such as atopic dermatitis (AD). Although IL-27 is linked to AD, its role and clinical significance in itch remain undefined. We sought to investigate IL-27 function in itch using tissue-specific transgenic mice, various itch models, behavior scoring, RNA sequencing, and cytokine/kinase array. Our findings show that IL-27 receptors were overexpressed in human AD skin. Intradermal IL-27 injection failed to directly induce itch in mice but upregulated skin protease-activated receptor 2 (PAR2) transcripts, a key factor in itch and AD. IL-27 activated human keratinocytes, increasing PAR2 transcription and activity. Coinjection of SLIGRL (PAR2 agonist) and IL-27 in mice heightened PAR2-mediated itch. In addition, IL-27 boosted BST2 transcription in sensory neurons and keratinocytes. BST2 was upregulated in AD skin, and its injection in mice induced itch-like response. BST2 colocalized with sensory nerve branches in AD skin from both human and murine models. Sensory neurons released BST2, and mice with sensory neuron-specific BST2 knockout displayed reduced itch responses. Overall, this study provides evidence that skin IL-27/PAR2 and neuronal IL-27/BST2 axes are implicated in cutaneous inflammation and pruritus. The discovery of neuronal BST2 in pruritus shed light on BST2 in the itch cascade.
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Affiliation(s)
- Yanqing Li
- School of Life Sciences, Henan University, Henan, China
| | - Weiwei Chen
- School of Life Sciences, Henan University, Henan, China
| | - Xingyun Zhu
- School of Life Sciences, Henan University, Henan, China
| | - Huiyuan Mei
- School of Life Sciences, Henan University, Henan, China
| | - Martin Steinhoff
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Department of Dermatology, Weill Cornell Medicine-Qatar, Doha, Qatar; College of Medicine, Qatar University, Doha, Qatar; Israel Englander Department of Dermatology, Weill Cornell Medicine, New York, New York, USA
| | - Joerg Buddenkotte
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Jinhai Wang
- School of Life Sciences, Henan University, Henan, China
| | - Wenhao Zhang
- School of Life Sciences, Henan University, Henan, China
| | - Zhenghui Li
- Department of Neurosurgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaolong Dai
- School of Life Sciences, Henan University, Henan, China
| | - Chunxu Shan
- School of Biotechnology, Faculty of Science and Health, Dublin City University, Dublin, Ireland
| | - Jiafu Wang
- School of Biotechnology, Faculty of Science and Health, Dublin City University, Dublin, Ireland
| | - Jianghui Meng
- School of Biotechnology, Faculty of Science and Health, Dublin City University, Dublin, Ireland.
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4
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Go EJ, Lee JY, Kim YH, Park CK. Site-Specific Transient Receptor Potential Channel Mechanisms and Their Characteristics for Targeted Chronic Itch Treatment. Biomolecules 2024; 14:107. [PMID: 38254707 PMCID: PMC10813675 DOI: 10.3390/biom14010107] [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: 12/28/2023] [Revised: 01/10/2024] [Accepted: 01/13/2024] [Indexed: 01/24/2024] Open
Abstract
Chronic itch is a debilitating condition with limited treatment options, severely affecting quality of life. The identification of pruriceptors has sparked a growing interest in the therapeutic potential of TRP channels in the context of itch. In this regard, we provided a comprehensive overview of the site-specific expression of TRP channels and their associated functions in response to a range of pruritogens. Although several potent antipruritic compounds that target specific TRP channels have been developed and have demonstrated efficacy in various chronic itch conditions through experimental means, a more thorough understanding of the potential for adverse effects or interactions with other TRP channels or GPCRs is necessary to develop novel and selective therapeutics that target TRP channels for treating chronic itch. This review focuses on the mechanism of itch associated with TRP channels at specific sites, from the skin to the sensory neuron, with the aim of suggesting specific therapeutic targets for treating this condition.
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Affiliation(s)
- Eun Jin Go
- Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea;
| | - Ji Yeon Lee
- Department of Anesthesiology and Pain Medicine, Gil Medical Center, Gachon University, Incheon 21565, Republic of Korea;
| | - Yong Ho Kim
- Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea;
| | - Chul-Kyu Park
- Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea;
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5
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Kim HJ, Kim SY, Bae HJ, Choi YY, An JY, Cho YE, Cho SY, Lee SJ, Lee S, Sin M, Yun YM, Lee JR, Park SJ. Anti-Inflammatory Effects of the LK5 Herbal Complex on LPS- and IL-4/IL-13-Stimulated HaCaT Cells and a DNCB-Induced Animal Model of Atopic Dermatitis in BALB/c Mice. Pharmaceutics 2023; 16:40. [PMID: 38258052 PMCID: PMC10821371 DOI: 10.3390/pharmaceutics16010040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 01/24/2024] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease influenced by a complex interplay of genetic and environmental factors. The activation of the JAK-STAT pathway increases the expression of inflammatory cytokines such as IL-4 and IL-13, further deteriorating AD. Therefore, for the treatment of AD, the JAK-STAT pathway is emerging as a significant target, alongside inflammatory cytokines. This study investigates the potential therapeutic effects of a novel herbal complex, LK5, composed of Scutellaria baicalensis, Liriope platyphylla, Sophora flavescens, Dictammus dasycarpus, and Phellodendron schneider, known for their anti-inflammatory and immune-modulating properties. We examined the anti-inflammatory and anti-AD effects of the LK5 herbal complex in HaCaT cells stimulated by LPS and IL-4/IL-13, as well as in a mouse model of AD induced by DNCB. In HaCaT cells stimulated with LPS or IL-4/IL-13, the LK5 herbal complex demonstrated anti-inflammatory effects by inhibiting the expression of inflammatory cytokines including TNF-α, IL-6, and IL-1β, and downregulating the phosphorylation of STAT proteins. In a murine AD-like model induced by DNCB, administration of the LK5 herbal complex significantly ameliorated clinical symptoms, including dermatitis, ear thickness, and TEWL. Histological analysis revealed a reduction in epidermal thickness and mast cell infiltration. The LK5 herbal complex also inhibited pruritus induced by compound 48/80. Furthermore, the LK5 herbal complex treatment significantly decreased the levels of inflammatory cytokines such as TSLP, IL-6, and IgE in plasma and ear tissue of AD-induced mice. These findings suggest that the LK5 herbal complex may modulate the immune response and alleviate AD symptoms by inhibiting STAT pathways.
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Affiliation(s)
- Hyun-Jeong Kim
- Department of Food Biotechnology and Environmental Science, Kangwon National University, Chuncheon 24341, Republic of Korea; (H.-J.K.); (Y.-Y.C.); (J.-Y.A.); (Y.E.C.); (S.-Y.C.); (S.-J.L.)
| | - So-Yeon Kim
- Department of Food Biotechnology and Environmental Science, Kangwon National University, Chuncheon 24341, Republic of Korea; (H.-J.K.); (Y.-Y.C.); (J.-Y.A.); (Y.E.C.); (S.-Y.C.); (S.-J.L.)
| | - Ho Jung Bae
- Agriculture and Life Science Research Institute, Kangwon National University, Chuncheon 24341, Republic of Korea;
| | - Yu-Yeong Choi
- Department of Food Biotechnology and Environmental Science, Kangwon National University, Chuncheon 24341, Republic of Korea; (H.-J.K.); (Y.-Y.C.); (J.-Y.A.); (Y.E.C.); (S.-Y.C.); (S.-J.L.)
| | - Ju-Yeon An
- Department of Food Biotechnology and Environmental Science, Kangwon National University, Chuncheon 24341, Republic of Korea; (H.-J.K.); (Y.-Y.C.); (J.-Y.A.); (Y.E.C.); (S.-Y.C.); (S.-J.L.)
| | - Ye Eun Cho
- Department of Food Biotechnology and Environmental Science, Kangwon National University, Chuncheon 24341, Republic of Korea; (H.-J.K.); (Y.-Y.C.); (J.-Y.A.); (Y.E.C.); (S.-Y.C.); (S.-J.L.)
| | - So-Young Cho
- Department of Food Biotechnology and Environmental Science, Kangwon National University, Chuncheon 24341, Republic of Korea; (H.-J.K.); (Y.-Y.C.); (J.-Y.A.); (Y.E.C.); (S.-Y.C.); (S.-J.L.)
| | - Su-Jung Lee
- Department of Food Biotechnology and Environmental Science, Kangwon National University, Chuncheon 24341, Republic of Korea; (H.-J.K.); (Y.-Y.C.); (J.-Y.A.); (Y.E.C.); (S.-Y.C.); (S.-J.L.)
| | - Sanghyun Lee
- Department of Plant Science and Technology, Chung-Ang University, Anseong 17546, Republic of Korea;
| | - MinSub Sin
- LK Co., Ltd., Hwaseong 18469, Republic of Korea; (M.S.); (Y.M.Y.); (J.R.L.)
| | - Young Min Yun
- LK Co., Ltd., Hwaseong 18469, Republic of Korea; (M.S.); (Y.M.Y.); (J.R.L.)
| | - Jong Ryul Lee
- LK Co., Ltd., Hwaseong 18469, Republic of Korea; (M.S.); (Y.M.Y.); (J.R.L.)
| | - Se Jin Park
- Department of Food Biotechnology and Environmental Science, Kangwon National University, Chuncheon 24341, Republic of Korea; (H.-J.K.); (Y.-Y.C.); (J.-Y.A.); (Y.E.C.); (S.-Y.C.); (S.-J.L.)
- Agriculture and Life Science Research Institute, Kangwon National University, Chuncheon 24341, Republic of Korea;
- School of Natural Resources and Environmental Sciences, Kangwon National University, Chuncheon 24341, Republic of Korea
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6
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Koumaki D, Gregoriou S, Evangelou G, Krasagakis K. Pruritogenic Mediators and New Antipruritic Drugs in Atopic Dermatitis. J Clin Med 2023; 12:2091. [PMID: 36983094 PMCID: PMC10054239 DOI: 10.3390/jcm12062091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/27/2023] [Accepted: 03/01/2023] [Indexed: 03/30/2023] Open
Abstract
Atopic dermatitis (AD) is a common highly pruritic chronic inflammatory skin disorder affecting 5-20% of children worldwide, while the prevalence in adults varies from 7 to 10%. Patients with AD experience intense pruritus that could lead to sleep disturbance and impaired quality of life. Here, we analyze the pathophysiology of itchiness in AD. We extensively review the histamine-dependent and histamine-independent pruritogens. Several receptors, substance P, secreted molecules, chemokines, and cytokines are involved as mediators in chronic itch. We also, summarize the new emerging antipruritic drugs in atopic dermatitis.
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Affiliation(s)
- Dimitra Koumaki
- Dermatology Department, University Hospital of Heraklion, 71110 Heraklion, Greece
| | - Stamatios Gregoriou
- Department of Dermatology and Venereology, Andreas Sygros Hospital, Medical School of Athens, National and Kapodistrian University of Athens, 16121 Athens, Greece
| | - George Evangelou
- Dermatology Department, University Hospital of Heraklion, 71110 Heraklion, Greece
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7
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Jung K, Pawluk MA, Lane M, Nabai L, Granville DJ. Granzyme B in Epithelial Barrier Dysfunction and Related Skin Diseases. Am J Physiol Cell Physiol 2022; 323:C170-C189. [PMID: 35442832 DOI: 10.1152/ajpcell.00052.2022] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The predominant function of the skin is to serve as a barrier - to protect against external insults and to prevent water loss. Junctional and structural proteins in the stratum corneum, the outermost layer of the epidermis, are critical to the integrity of the epidermal barrier as it balances ongoing outward migration, differentiation, and desquamation of keratinocytes in the epidermis. As such, epidermal barrier function is highly susceptible to upsurges of proteolytic activity in the stratum corneum and epidermis. Granzyme B is a serine protease scarce in healthy tissues but present at high levels in tissues encumbered by chronic inflammation. Discovered in the 1980s, Granzyme B is currently recognized for its intracellular roles in immune cell-mediated targeted apoptosis as well as extracellular roles in inflammation, chronic injuries, tissue remodeling, and processing of cytokines, matrix proteins, and autoantigens. Increasing evidence has emerged in recent years supporting a role for Granzyme B in promoting barrier dysfunction in the epidermis by direct cleavage of barrier proteins and eliciting immunoreactivity. Likewise, Granzyme B contributes to impaired epithelial function of the airways, retina, gut and vessels. In the present review, the role of Granzyme B in cutaneous epithelial dysfunction is discussed in the context of specific conditions with an overview of underlying mechanisms as well as utility of current experimental and therapeutic inhibitors.
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Affiliation(s)
- Karen Jung
- International Collaboration on Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.,British Columbia Professional Firefighters' Wound Healing Laboratory, VCHRI, Vancouver, British Columbia, Canada
| | - Megan A Pawluk
- International Collaboration on Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.,British Columbia Professional Firefighters' Wound Healing Laboratory, VCHRI, Vancouver, British Columbia, Canada
| | - Michael Lane
- International Collaboration on Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.,British Columbia Professional Firefighters' Wound Healing Laboratory, VCHRI, Vancouver, British Columbia, Canada
| | - Layla Nabai
- International Collaboration on Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.,British Columbia Professional Firefighters' Wound Healing Laboratory, VCHRI, Vancouver, British Columbia, Canada
| | - David J Granville
- International Collaboration on Repair Discoveries (ICORD), Vancouver Coastal Health Research Institute (VCHRI), University of British Columbia (UBC), Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.,British Columbia Professional Firefighters' Wound Healing Laboratory, VCHRI, Vancouver, British Columbia, Canada
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8
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Hasegawa T, Oka T, Demehri S. Alarmin Cytokines as Central Regulators of Cutaneous Immunity. Front Immunol 2022; 13:876515. [PMID: 35432341 PMCID: PMC9005840 DOI: 10.3389/fimmu.2022.876515] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 03/08/2022] [Indexed: 12/13/2022] Open
Abstract
Skin acts as the primary interface between the body and the environment. The skin immune system is composed of a complex network of immune cells and factors that provide the first line of defense against microbial pathogens and environmental insults. Alarmin cytokines mediate an intricate intercellular communication between keratinocytes and immune cells to regulate cutaneous immune responses. Proper functions of the type 2 alarmin cytokines, thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33, are paramount to the maintenance of skin homeostasis, and their dysregulation is commonly associated with allergic inflammation. In this review, we discuss recent findings on the complex regulatory network of type 2 alarmin cytokines that control skin immunity and highlight the mechanisms by which these cytokines regulate skin immune responses in host defense, chronic inflammation, and cancer.
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Affiliation(s)
| | - Tomonori Oka
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Shadmehr Demehri
- Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
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9
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Redhu D, Franke K, Aparicio-Soto M, Kumari V, Pazur K, Illerhaus A, Hartmann K, Worm M, Babina M. Mast cells instruct keratinocytes to produce TSLP - relevance of the tryptase/PAR-2 axis. J Allergy Clin Immunol 2022; 149:2053-2061.e6. [PMID: 35240143 DOI: 10.1016/j.jaci.2022.01.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 11/29/2021] [Accepted: 01/07/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Thymic stromal lymphopoietin (TSLP) promotes Th2 inflammation and is deeply intertwined with inflammatory dermatoses like atopic dermatitis. The mechanisms regulating TSLP are poorly defined. OBJECTIVE To investigate whether and by what mechanisms mast cells (MCs) foster TSLP responses in the cutaneous environment. METHODS Ex vivo and in vivo skin MC degranulation was induced by compound 48/80 in wildtype, PAR-2- and MC-deficient mice in the presence/absence of neutralizing antibodies, antagonists or exogenous mMCP6. Primary human keratinocytes (hKCs) and murine skin explants (mSEs) were stimulated with lysates/supernatants of human skin MCs, purified tryptase or MC-lysate diminished of tryptase. Chymase and histamine were also used. TSLP was quantified by ELISA, RT-qPCR and immunofluorescence staining. RESULTS Mrgprb2-activation elicited TSLP in intact skin, mainly in the epidermis. Responses were strictly MC-dependent and relied on PAR-2. Complementarily, TSLP was elicited by tryptase in mSEs. Exogenous mMCP6 could fully restore responsiveness in MC-deficient mSEs. Conversely, PAR-2-knockout mice were unresponsive to mMCP6, while displaying increased responsiveness to other inflammatory pathways, e.g. IL-1α. Indeed, IL-1α acted in concert with tryptase. In hKCs, MC-elicited TSLP generation was likewise abolished by tryptase inhibition or elimination. Chymase and histamine did not impact TSLP production, but histamine triggered IL-6, IL-8, and SCF. CONCLUSION MCs communicate with KCs more broadly than hitherto suspected. The tryptase-PAR-2 axis is a crucial component of this crosstalk, underlying MC-dependent stimulation of TSLP in neighboring KCs. Interference specifically with MC tryptase may offer a treatment option for disorders initiated or perpetuated by aberrant TSLP, such as atopic dermatitis. CLINICAL IMPLICATIONS Awareness of the crosstalk between MCs and KCs may permit improved management of skin disorders, e.g. by selective targeting of tryptase.
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Affiliation(s)
- Davender Redhu
- Department of Dermatology and Allergy, Allergy Center Charité, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Kristin Franke
- Department of Dermatology and Allergy, Allergy Center Charité, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Marina Aparicio-Soto
- Department of Dermatology and Allergy, Allergy Center Charité, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Vandana Kumari
- Department of Dermatology and Allergy, Allergy Center Charité, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Kristijan Pazur
- Department of Dermatology and Allergy, Allergy Center Charité, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Anja Illerhaus
- Department of Dermatology and Venerology, University of Cologne, Cologne, Germany
| | - Karin Hartmann
- Department of Dermatology, Division of Allergy, University Hospital Basel and University of Basel, Basel, Switzerland; Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Margitta Worm
- Department of Dermatology and Allergy, Allergy Center Charité, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
| | - Magda Babina
- Department of Dermatology and Allergy, Allergy Center Charité, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
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10
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Guo CJ, Grabinski NS, Liu Q. Peripheral Mechanisms of Itch. J Invest Dermatol 2021; 142:31-41. [PMID: 34838258 DOI: 10.1016/j.jid.2021.10.024] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 10/15/2021] [Accepted: 10/26/2021] [Indexed: 12/30/2022]
Abstract
Itch is a universally experienced sensation, and chronic itch can be as diabolically debilitating as pain. Recent advances have not only identified the neuronal itch sensing circuitry, but also have uncovered the intricate interactions between skin and immune cells that work together with neurons to identify itch-inducing irritants. In this review, we will summarize the fundamental mechanisms of acute itch detection in the skin, as well as highlight the recent discoveries relating to this topic.
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Affiliation(s)
- Changxiong J Guo
- Center for the Study of Itch & Sensory Disorders, Department of Anesthesiology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Nathaniel S Grabinski
- Center for the Study of Itch & Sensory Disorders, Department of Anesthesiology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Qin Liu
- Center for the Study of Itch & Sensory Disorders, Department of Anesthesiology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
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11
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The Pathology of Type 2 Inflammation-Associated Itch in Atopic Dermatitis. Diagnostics (Basel) 2021; 11:diagnostics11112090. [PMID: 34829437 PMCID: PMC8618746 DOI: 10.3390/diagnostics11112090] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 11/06/2021] [Accepted: 11/09/2021] [Indexed: 12/20/2022] Open
Abstract
Accumulated evidence on type 2 inflammation-associated itch in atopic dermatitis has recently been reported. Crosstalk between the immune and nervous systems (neuroimmune interactions) is prominent in atopic dermatitis research, particularly regarding itch and inflammation. A comprehensive understanding of bidirectional neuroimmune interactions will provide insights into the pathogenesis of itch and its treatment. There is currently no agreed cure for itch in atopic dermatitis; however, increasing numbers of novel and targeted biologic agents have potential for its management and are in the advanced stages of clinical trials. In this review, we summarize and discuss advances in our understanding of type 2 inflammation-associated itch and implications for its management and treatment in patients with atopic dermatitis.
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12
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Common and discrete mechanisms underlying chronic pain and itch: peripheral and central sensitization. Pflugers Arch 2021; 473:1603-1615. [PMID: 34245379 DOI: 10.1007/s00424-021-02599-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 05/26/2021] [Accepted: 06/22/2021] [Indexed: 12/30/2022]
Abstract
Normally, an obvious antagonism exists between pain and itch. In normal conditions, painful stimuli suppress itch sensation, whereas pain killers often generate itch. Although pain and itch are mediated by separate pathways under normal conditions, most chemicals are not highly specific to one sensation in chronic pathologic conditions. Notably, in patients with neuropathic pain, histamine primarily induces pain rather than itch, while in patients with atopic dermatitis, bradykinin triggers itch rather than pain. Accordingly, repetitive scratching even enhances itch sensation in chronic itch conditions. Physicians often prescribe pain relievers to patients with chronic itch, suggesting common mechanisms underlying chronic pain and itch, especially peripheral and central sensitization. Rather than separating itch and pain, studies should investigate chronic itch and pain including neuropathic and inflammatory conditions. Here, we reviewed chronic sensitization leading to chronic pain and itch at both peripheral and central levels. Studies investigating the connection between pain and itch facilitate the development of new therapeutics against both chronic dysesthesias based on the underlying pathophysiology.
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13
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Wong LS, Yen YT, Lee CH. The Implications of Pruritogens in the Pathogenesis of Atopic Dermatitis. Int J Mol Sci 2021; 22:7227. [PMID: 34281281 PMCID: PMC8269281 DOI: 10.3390/ijms22137227] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 06/29/2021] [Accepted: 07/01/2021] [Indexed: 01/17/2023] Open
Abstract
Atopic dermatitis (AD) is a prototypic inflammatory disease that presents with intense itching. The pathophysiology of AD is multifactorial, involving environmental factors, genetic susceptibility, skin barrier function, and immune responses. A recent understanding of pruritus transmission provides more information about the role of pruritogens in the pathogenesis of AD. There is evidence that pruritogens are not only responsible for eliciting pruritus, but also interact with immune cells and act as inflammatory mediators, which exacerbate the severity of AD. In this review, we discuss the interaction between pruritogens and inflammatory molecules and summarize the targeted therapies for AD.
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Affiliation(s)
- Lai-San Wong
- Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan;
| | - Yu-Ta Yen
- Department of Dermatology, Fooying University Hospital, Pingtung 928, Taiwan;
| | - Chih-Hung Lee
- Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan;
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14
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Chun PIF, Lehman H. Current and Future Monoclonal Antibodies in the Treatment of Atopic Dermatitis. Clin Rev Allergy Immunol 2021; 59:208-219. [PMID: 32617839 DOI: 10.1007/s12016-020-08802-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Atopic dermatitis is a common immunologic skin disease. Mild atopic dermatitis can be managed with emollients and topical therapies such as low potency topical steroids, which have a favorable safety profile. Severe atopic dermatitis, in contrast, is a challenging disease to treat. Topical therapies are typically inadequate for control of severe atopic dermatitis. When topical therapies fail, the mainstay of therapy for severe atopic dermatitis has traditionally been phototherapy or off-label use of systemic immunosuppressant treatment, yet systemic immunosuppressants all have significant potential toxicities, drug interactions, and contraindications, requiring close monitoring. Targeted biologics are therefore attractive treatment options for topical therapy-refractory cases of atopic dermatitis, with the potential to offer effective, safer treatment of uncontrolled atopic dermatitis. Dupilumab, as the only biologic therapy currently FDA-approved for atopic dermatitis, is effective for many patients, but there is need for continuing study of additional biologic therapies to address the needs of diverse patients with uncontrolled atopic dermatitis.
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Affiliation(s)
- Peter Ip Fung Chun
- Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Heather Lehman
- Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. .,Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, 1001 Main Street, Buffalo, NY, 14203, USA.
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15
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Umehara Y, Kiatsurayanon C, Trujillo-Paez JV, Chieosilapatham P, Peng G, Yue H, Nguyen HLT, Song P, Okumura K, Ogawa H, Niyonsaba F. Intractable Itch in Atopic Dermatitis: Causes and Treatments. Biomedicines 2021; 9:biomedicines9030229. [PMID: 33668714 PMCID: PMC7996203 DOI: 10.3390/biomedicines9030229] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/18/2021] [Accepted: 02/19/2021] [Indexed: 11/16/2022] Open
Abstract
Itch or pruritus is the hallmark of atopic dermatitis and is defined as an unpleasant sensation that evokes the desire to scratch. It is also believed that itch is a signal of danger from various environmental factors or physiological abnormalities. Because histamine is a well-known substance inducing itch, H1-antihistamines are the most frequently used drugs to treat pruritus. However, H1-antihistamines are not fully effective against intractable itch in patients with atopic dermatitis. Given that intractable itch is a clinical problem that markedly decreases quality of life, its treatment in atopic dermatitis is of high importance. Histamine-independent itch may be elicited by various pruritogens, including proteases, cytokines, neuropeptides, lipids, and opioids, and their cognate receptors, such as protease-activated receptors, cytokine receptors, Mas-related G protein-coupled receptors, opioid receptors, and transient receptor potential channels. In addition, cutaneous hyperinnervation is partly involved in itch sensitization in the periphery. It is believed that dry skin is a key feature of intractable itch in atopic dermatitis. Treatment of the underlying conditions that cause itch is necessary to improve the quality of life of patients with atopic dermatitis. This review describes current insights into the pathophysiology of itch and its treatment in atopic dermatitis.
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Affiliation(s)
- Yoshie Umehara
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; (Y.U.); (J.V.T.-P.); (G.P.); (H.Y.); (H.L.T.N.); (K.O.); (H.O.)
| | - Chanisa Kiatsurayanon
- Institute of Dermatology, Department of Medical Services, Ministry of Public Health, Bangkok 10400, Thailand;
| | - Juan Valentin Trujillo-Paez
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; (Y.U.); (J.V.T.-P.); (G.P.); (H.Y.); (H.L.T.N.); (K.O.); (H.O.)
| | - Panjit Chieosilapatham
- Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Ge Peng
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; (Y.U.); (J.V.T.-P.); (G.P.); (H.Y.); (H.L.T.N.); (K.O.); (H.O.)
| | - Hainan Yue
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; (Y.U.); (J.V.T.-P.); (G.P.); (H.Y.); (H.L.T.N.); (K.O.); (H.O.)
| | - Hai Le Thanh Nguyen
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; (Y.U.); (J.V.T.-P.); (G.P.); (H.Y.); (H.L.T.N.); (K.O.); (H.O.)
| | - Pu Song
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China;
| | - Ko Okumura
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; (Y.U.); (J.V.T.-P.); (G.P.); (H.Y.); (H.L.T.N.); (K.O.); (H.O.)
| | - Hideoki Ogawa
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; (Y.U.); (J.V.T.-P.); (G.P.); (H.Y.); (H.L.T.N.); (K.O.); (H.O.)
| | - François Niyonsaba
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; (Y.U.); (J.V.T.-P.); (G.P.); (H.Y.); (H.L.T.N.); (K.O.); (H.O.)
- Faculty of International Liberal Arts, Juntendo University, Tokyo 113-8421, Japan
- Correspondence: ; Tel.: +81-3-5802-1591; Fax: +81-3-3813-5512
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16
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Ruppenstein A, Limberg MM, Loser K, Kremer AE, Homey B, Raap U. Involvement of Neuro-Immune Interactions in Pruritus With Special Focus on Receptor Expressions. Front Med (Lausanne) 2021; 8:627985. [PMID: 33681256 PMCID: PMC7930738 DOI: 10.3389/fmed.2021.627985] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 01/27/2021] [Indexed: 12/21/2022] Open
Abstract
Pruritus is a common, but very challenging symptom with a wide diversity of underlying causes like dermatological, systemic, neurological and psychiatric diseases. In dermatology, pruritus is the most frequent symptom both in its acute and chronic form (over 6 weeks in duration). Treatment of chronic pruritus often remains challenging. Affected patients who suffer from moderate to severe pruritus have a significantly reduced quality of life. The underlying physiology of pruritus is very complex, involving a diverse network of components in the skin including resident cells such as keratinocytes and sensory neurons as well as transiently infiltrating cells such as certain immune cells. Previous research has established that there is a significant crosstalk among the stratum corneum, nerve fibers and various immune cells, such as keratinocytes, T cells, basophils, eosinophils and mast cells. In this regard, interactions between receptors on cutaneous and spinal neurons or on different immune cells play an important role in the processing of signals which are important for the transmission of pruritus. In this review, we discuss the role of various receptors involved in pruritus and inflammation, such as TRPV1 and TRPA1, IL-31RA and OSMR, TSLPR, PAR-2, NK1R, H1R and H4R, MRGPRs as well as TrkA, with a focus on interaction between nerve fibers and different immune cells. Emerging evidence shows that neuro-immune interactions play a pivotal role in mediating pruritus-associated inflammatory skin diseases such as atopic dermatitis, psoriasis or chronic spontaneous urticaria. Targeting these bidirectional neuro-immune interactions and the involved pruritus-specific receptors is likely to contribute to novel insights into the underlying pathogenesis and targeted treatment options of pruritus.
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Affiliation(s)
- Aylin Ruppenstein
- Division of Experimental Allergy and Immunodermatology, Faculty of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany
| | - Maren M Limberg
- Division of Experimental Allergy and Immunodermatology, Faculty of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany
| | - Karin Loser
- Division of Immunology, Faculty of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany
| | - Andreas E Kremer
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Bernhard Homey
- Department of Dermatology, Heinrich-Heine-University of Düsseldorf, Düsseldorf, Germany
| | - Ulrike Raap
- Division of Experimental Allergy and Immunodermatology, Faculty of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany.,University Clinic of Dermatology and Allergy, Oldenburg Clinic, Oldenburg, Germany
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17
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Gilhar A, Reich K, Keren A, Kabashima K, Steinhoff M, Paus R. Mouse models of atopic dermatitis: a critical reappraisal. Exp Dermatol 2021; 30:319-336. [PMID: 33368555 DOI: 10.1111/exd.14270] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/17/2020] [Accepted: 12/17/2020] [Indexed: 12/13/2022]
Abstract
Mouse models for atopic dermatitis (AD) are an indispensable preclinical research tool for testing new candidate AD therapeutics and for interrogating AD pathobiology in vivo. In this Viewpoint, we delineate why, unfortunately, none of the currently available so-called "AD" mouse models satisfactorily reflect the clinical complexity of human AD, but imitate more "allergic" or "irriant" contact dermatitis conditions. This limits the predictive value of AD models for clinical outcomes of new tested candidate AD therapeutics and the instructiveness of mouse models for human AD pathophysiology research. Here, we propose to initiate a rational debate on the minimal criteria that a mouse model should meet in order to be considered relevant for human AD. We suggest that valid AD models should at least meet the following criteria: (a) an AD-like epidermal barrier defect with reduced filaggrin expression along with hyperproliferation, hyperplasia; (b) increased epidermal expression of thymic stromal lymphopoietin (TSLP), periostin and/or chemokines such as TARC (CCL17); (c) a characteristic dermal immune cell infiltrate with overexpression of some key cytokines such as IL-4, IL-13, IL-31 and IL-33; (d) distinctive "neurodermatitis" features (sensory skin hyperinnervation, defective beta-adrenergic signalling, neurogenic skin inflammation and triggering or aggravation of AD-like skin lesions by perceived stress); and (e) response of experimentally induced skin lesions to standard AD therapy. Finally, we delineate why humanized AD mouse models (human skin xenotransplants on SCID mice) offer a particularly promising preclinical research alternative to the currently available "AD" mouse models.
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Affiliation(s)
- Amos Gilhar
- Skin Research Laboratory, Rappaport Faculty of Medicine, Technion -Israel Institute of Technology, Haifa, Israel.,Rambam Health Care Campus, Haifa, Israel
| | - Kristian Reich
- Centre for Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Skinflammation Center, Hamburg, Germany
| | - Aviad Keren
- Skin Research Laboratory, Rappaport Faculty of Medicine, Technion -Israel Institute of Technology, Haifa, Israel
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Singapore Immunology Network (SIgN) and Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore
| | - Martin Steinhoff
- Department of Dermatology and Venereology, Hamad Medical Corporation, Qatar University, Doha, Qatar.,School of Medicine, Weill Cornell University-Qatar and Qatar University, Doha, Qatar
| | - Ralf Paus
- Dr. Phillip Frost, Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,Dermatology Research Centre, University of Manchester and NIHR Manchester Biomedical Research Centre, Manchester, UK.,Monasterium Laboratory, Münster, Germany
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18
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Patrick GJ, Archer NK, Miller LS. Which Way Do We Go? Complex Interactions in Atopic Dermatitis Pathogenesis. J Invest Dermatol 2020; 141:274-284. [PMID: 32943210 DOI: 10.1016/j.jid.2020.07.006] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/02/2020] [Accepted: 07/06/2020] [Indexed: 02/07/2023]
Abstract
Atopic dermatitis (AD) is a common, chronic, inflammatory skin condition characterized by recurrent and pruritic skin eruptions. Multiple factors contribute to the pathogenesis of AD, including skin barrier dysfunction, microbial dysbiosis, and immune dysregulation. Interactions among these factors form a complex, multidirectional network that can reinforce atopic skin disease but can also be ameliorated by targeted therapies. This review summarizes the complex interactions among contributing factors in AD and the implications on disease development and therapeutic interventions.
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Affiliation(s)
- Garrett J Patrick
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Nathan K Archer
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Lloyd S Miller
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Janssen Research and Development, Spring House, Pennsylvania, USA.
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19
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Frombach J, Rancan F, Kübrich K, Schumacher F, Unbehauen M, Blume-Peytavi U, Haag R, Kleuser B, Sabat R, Wolk K, Vogt A. Serine Protease-Mediated Cutaneous Inflammation: Characterization of an Ex Vivo Skin Model for the Assessment of Dexamethasone-Loaded Core Multishell-Nanocarriers. Pharmaceutics 2020; 12:pharmaceutics12090862. [PMID: 32927792 PMCID: PMC7558872 DOI: 10.3390/pharmaceutics12090862] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 09/02/2020] [Accepted: 09/07/2020] [Indexed: 11/29/2022] Open
Abstract
Standard experimental set-ups for the assessment of skin penetration are typically performed on skin explants with an intact skin barrier or after a partial mechanical or chemical perturbation of the stratum corneum, but they do not take into account biochemical changes. Among the various pathological alterations in inflamed skin, aberrant serine protease (SP) activity directly affects the biochemical environment in the superficial compartments, which interact with topically applied formulations. It further impacts the skin barrier structure and is a key regulator of inflammatory mediators. Herein, we used short-term cultures of ex vivo human skin treated with trypsin and plasmin as inflammatory stimuli to assess the penetration and biological effects of the anti-inflammatory drug dexamethasone (DXM), encapsulated in core multishell-nanocarriers (CMS-NC), when compared to a standard cream formulation. Despite a high interindividual variability, the combined pretreatment of the skin resulted in an average 2.5-fold increase of the transepidermal water loss and swelling of the epidermis, as assessed by optical coherence tomography, as well as in a moderate increase of a broad spectrum of proinflammatory mediators of clinical relevance. The topical application of DXM-loaded CMS-NC or DXM standard cream revealed an increased penetration into SP-treated skin when compared to untreated control skin with an intact barrier. Both formulations, however, delivered sufficient amounts of DXM to effectively suppress the production of interleukin-6 (IL-6), interleukin-8 (IL-8) and Thymic Stromal Lymphopoietin (TSLP). In conclusion, we suggest that the herein presented ex vivo inflammatory skin model is functional and could improve the selection of promising drug delivery strategies for anti-inflammatory compounds at early stages of development.
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Affiliation(s)
- Janna Frombach
- Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venereology and Allergy, Charité-Universitatsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (J.F.); (F.R.); (K.K.); (U.B.-P.)
| | - Fiorenza Rancan
- Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venereology and Allergy, Charité-Universitatsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (J.F.); (F.R.); (K.K.); (U.B.-P.)
| | - Katharina Kübrich
- Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venereology and Allergy, Charité-Universitatsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (J.F.); (F.R.); (K.K.); (U.B.-P.)
| | - Fabian Schumacher
- Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany; (F.S.); (B.K.)
| | - Michael Unbehauen
- Organic Chemistry, Institute of Chemistry and Biochemistry, Freie Universitaet Berlin, 14195 Berlin, Germany; (M.U.); (R.H.)
| | - Ulrike Blume-Peytavi
- Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venereology and Allergy, Charité-Universitatsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (J.F.); (F.R.); (K.K.); (U.B.-P.)
| | - Rainer Haag
- Organic Chemistry, Institute of Chemistry and Biochemistry, Freie Universitaet Berlin, 14195 Berlin, Germany; (M.U.); (R.H.)
| | - Burkhard Kleuser
- Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany; (F.S.); (B.K.)
| | - Robert Sabat
- Psoriasis Research and Treatment Center, Department of Dermatology, Venerology and Allergy/Institute for Medical Immunology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (R.S.); (K.W.)
| | - Kerstin Wolk
- Psoriasis Research and Treatment Center, Department of Dermatology, Venerology and Allergy/Institute for Medical Immunology, Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (R.S.); (K.W.)
| | - Annika Vogt
- Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venereology and Allergy, Charité-Universitatsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (J.F.); (F.R.); (K.K.); (U.B.-P.)
- Correspondence:
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20
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Oyesola OO, Früh SP, Webb LM, Tait Wojno ED. Cytokines and beyond: Regulation of innate immune responses during helminth infection. Cytokine 2020; 133:154527. [PMID: 30241895 PMCID: PMC6422760 DOI: 10.1016/j.cyto.2018.08.021] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 08/18/2018] [Accepted: 08/20/2018] [Indexed: 12/22/2022]
Abstract
Parasitic helminth infection elicits a type 2 cytokine-mediated inflammatory response. During type 2 inflammation, damaged or stimulated epithelial cells exposed to helminths and their products produce alarmins and cytokines including IL-25, IL-33, and thymic stromal lymphopoietin. These factors promote innate immune cell activation that supports the polarization of CD4+ T helper type 2 (Th2) cells. Activated innate and Th2 cells produce the cytokines IL-4, -5, -9, and -13 that perpetuate immune activation and act back on the epithelium to cause goblet cell hyperplasia and increased epithelial cell turnover. Together, these events facilitate worm expulsion and wound healing processes. While the role of Th2 cells in this context has been heavily studied, recent work has revealed that epithelial cell-derived cytokines are drivers of key innate immune responses that are critical for type 2 anti-helminth responses. Cutting-edge studies have begun to fully assess how other factors and pathways, including lipid mediators, chemokines, Fc receptor signaling, danger-associated molecular pattern molecules, and direct cell-cell interactions, also participate in shaping innate cell-mediated type 2 inflammation. In this review, we discuss how these pathways intersect and synergize with pathways controlled by epithelial cell-derived cytokines to coordinate innate immune responses that drive helminth-induced type 2 inflammation.
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Affiliation(s)
- Oyebola O Oyesola
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Simon P Früh
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Lauren M Webb
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, USA
| | - Elia D Tait Wojno
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, USA.
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21
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Buhl T, Ikoma A, Kempkes C, Cevikbas F, Sulk M, Buddenkotte J, Akiyama T, Crumrine D, Camerer E, Carstens E, Schön MP, Elias P, Coughlin SR, Steinhoff M. Protease-Activated Receptor-2 Regulates Neuro-Epidermal Communication in Atopic Dermatitis. Front Immunol 2020; 11:1740. [PMID: 32903402 PMCID: PMC7435019 DOI: 10.3389/fimmu.2020.01740] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 06/29/2020] [Indexed: 01/01/2023] Open
Abstract
Background: Activation of protease-activated receptor-2 (PAR2) has been implicated in inflammation, pruritus, and skin barrier regulation, all characteristics of atopic dermatitis (AD), as well as Netherton syndrome which has similar characteristics. However, understanding the precise role of PAR2 on neuro-immune communication in AD has been hampered by the lack of appropriate animal models. Methods: We used a recently established mouse model with epidermal overexpression of PAR2 (PAR2OE) and littermate WT mice to study the impact of increased PAR2 expression in epidermal cells on spontaneous and house dust mite (HDM)-induced skin inflammation, itch, and barrier dysfunction in AD, in vivo and ex vivo. Results: PAR2OE newborns displayed no overt abnormalities, but spontaneously developed dry skin, severe pruritus, and eczema. Dermatological, neurophysiological, and immunological analyses revealed the hallmarks of AD-like skin disease. Skin barrier defects were observed before onset of skin lesions. Application of HDM onto PAR2OE mice triggered pruritus and the skin phenotype. PAR2OE mice displayed an increased density of nerve fibers, increased nerve growth factor and endothelin-1 expression levels, alloknesis, enhanced scratching (hyperknesis), and responses of dorsal root ganglion cells to non-histaminergic pruritogens. Conclusion: PAR2 in keratinocytes, activated by exogenous and endogenous proteases, is sufficient to drive barrier dysfunction, inflammation, and pruritus and sensitize skin to the effects of HDM in a mouse model that mimics human AD. PAR2 signaling in keratinocytes appears to be sufficient to drive several levels of neuro-epidermal communication, another feature of human AD.
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Affiliation(s)
- Timo Buhl
- Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA, United States.,Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany
| | - Akihiko Ikoma
- Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA, United States.,Department of Dermatology and UCD Charles Institute for Translational Dermatology, University College Dublin, Dublin, Ireland
| | - Cordula Kempkes
- Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Ferda Cevikbas
- Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Mathias Sulk
- Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA, United States.,Department of Dermatology, University Hospital Münster, Münster, Germany
| | - Joerg Buddenkotte
- Department of Dermatology and Venerology, Hamad Medical Corporation, Doha, Qatar.,Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Tasuku Akiyama
- Department of Dermatology, Anatomy and Cell Biology, Temple Itch Center, Temple University, Philadelphia, PA, United States.,Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, CA, United States
| | - Debbie Crumrine
- Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Eric Camerer
- INSERM U970, Paris Cardiovascular Research Centre, Paris, France
| | - Earl Carstens
- Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, CA, United States
| | - Michael P Schön
- Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany
| | - Peter Elias
- Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Shaun R Coughlin
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States
| | - Martin Steinhoff
- Department of Dermatology and Surgery, University of California, San Francisco, San Francisco, CA, United States.,Department of Dermatology and UCD Charles Institute for Translational Dermatology, University College Dublin, Dublin, Ireland.,Department of Dermatology and Venerology, Hamad Medical Corporation, Doha, Qatar.,Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.,Department of Dermatology, Medical School, University of Qatar, Doha, Qatar.,School of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar.,Department of Dermatology, Weill Cornell Medicine, New York, NY, United States
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22
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Muzumdar S, Koch M, Hiebert H, Bapst A, Gravina A, Bloch W, Beer HD, Werner S, Schäfer M. Genetic activation of Nrf2 reduces cutaneous symptoms in a murine model of Netherton syndrome. Dis Model Mech 2020; 13:dmm042648. [PMID: 32457102 PMCID: PMC7286291 DOI: 10.1242/dmm.042648] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 03/16/2020] [Indexed: 01/08/2023] Open
Abstract
Netherton syndrome is a monogenic autosomal recessive disorder primarily characterized by the detachment of the uppermost layer of the epidermis, the stratum corneum It results from mutations in the SPINK5 gene, which codes for a kallikrein inhibitor. Uncontrolled kallikrein activity leads to premature desquamation, resulting in a severe epidermal barrier defect and subsequent life-threatening systemic infections and chronic cutaneous inflammation. Here, we show that genetic activation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nfe2l2/Nrf2) in keratinocytes of Spink5 knockout mice, a model for Netherton syndrome, significantly alleviates their cutaneous phenotype. Nrf2 activation promoted attachment of the stratum corneum and concomitant epidermal barrier function, and reduced the expression of pro-inflammatory cytokines such as tumor necrosis factor α and thymic stromal lymphopoietin. Mechanistically, we show that Nrf2 activation induces overexpression of secretory leukocyte protease inhibitor (Slpi), a known inhibitor of kallikrein 7 and elastase 2, in mouse and human keratinocytes in vivo and in vitro, respectively. In the Spink5-deficient epidermis, the upregulation of Slpi is likely to promote stabilization of corneodesmosomes, thereby preventing premature desquamation. Our results suggest pharmacological NRF2 activation as a promising treatment modality for Netherton syndrome patients.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Sukalp Muzumdar
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Michael Koch
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Hayley Hiebert
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Andreas Bapst
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Alessia Gravina
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Wilhelm Bloch
- Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, 50933 Cologne, Germany
| | - Hans-Dietmar Beer
- Department of Dermatology, University Hospital of Zurich, Gloriastrasse 3, 8091 Zurich, Switzerland
| | - Sabine Werner
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Matthias Schäfer
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland
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23
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Nakajima S, Nomura T, Common J, Kabashima K. Insights into atopic dermatitis gained from genetically defined mouse models. J Allergy Clin Immunol 2019; 143:13-25. [PMID: 30612664 DOI: 10.1016/j.jaci.2018.11.014] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 11/14/2018] [Accepted: 11/16/2018] [Indexed: 01/01/2023]
Abstract
Atopic dermatitis (AD) is characterized by severe pruritus and recurrent eczema with a chronic disease course. Impaired skin barrier function, hyperactivated TH2 cell-type inflammation, and pruritus-induced scratching contribute to the disease pathogenesis of AD. Skin microbial alterations complicate the pathogenesis of AD further. Mouse models are a powerful tool to analyze such intricate pathophysiology of AD, with a caution that anatomy and immunology of the skin differ between human subjects and mice. Here we review recent understanding of AD etiology obtained using mouse models, which address the epidermal barrier, skin microbiome, TH2 immune response, and pruritus.
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Affiliation(s)
- Saeko Nakajima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takashi Nomura
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - John Common
- Skin Research Institute of Singapore (SRIS), Singapore.
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Skin Research Institute of Singapore (SRIS), Singapore; Singapore Immunology Network, A*STAR, Singapore.
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24
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Talavera K, Startek JB, Alvarez-Collazo J, Boonen B, Alpizar YA, Sanchez A, Naert R, Nilius B. Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease. Physiol Rev 2019; 100:725-803. [PMID: 31670612 DOI: 10.1152/physrev.00005.2019] [Citation(s) in RCA: 253] [Impact Index Per Article: 42.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The transient receptor potential ankyrin (TRPA) channels are Ca2+-permeable nonselective cation channels remarkably conserved through the animal kingdom. Mammals have only one member, TRPA1, which is widely expressed in sensory neurons and in non-neuronal cells (such as epithelial cells and hair cells). TRPA1 owes its name to the presence of 14 ankyrin repeats located in the NH2 terminus of the channel, an unusual structural feature that may be relevant to its interactions with intracellular components. TRPA1 is primarily involved in the detection of an extremely wide variety of exogenous stimuli that may produce cellular damage. This includes a plethora of electrophilic compounds that interact with nucleophilic amino acid residues in the channel and many other chemically unrelated compounds whose only common feature seems to be their ability to partition in the plasma membrane. TRPA1 has been reported to be activated by cold, heat, and mechanical stimuli, and its function is modulated by multiple factors, including Ca2+, trace metals, pH, and reactive oxygen, nitrogen, and carbonyl species. TRPA1 is involved in acute and chronic pain as well as inflammation, plays key roles in the pathophysiology of nearly all organ systems, and is an attractive target for the treatment of related diseases. Here we review the current knowledge about the mammalian TRPA1 channel, linking its unique structure, widely tuned sensory properties, and complex regulation to its roles in multiple pathophysiological conditions.
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Affiliation(s)
- Karel Talavera
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Justyna B Startek
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Julio Alvarez-Collazo
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Brett Boonen
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Yeranddy A Alpizar
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Alicia Sanchez
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Robbe Naert
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Bernd Nilius
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
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25
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Gür Çetinkaya P, Şahiner ÜM. Childhood atopic dermatitis: current developments, treatment approaches, and future expectations. Turk J Med Sci 2019; 49:963-984. [PMID: 31408293 PMCID: PMC7018348 DOI: 10.3906/sag-1810-105] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Atopic dermatitis (AD) is the most common chronic inflammatory skin disorder of childhood. Underlying factors that contribute to AD are impaired epithelial barrier, alterations in the lipid composition of the skin, immunological imbalance including increased Th2/Th1 ratio, proinflammatory cytokines, decreased T regulatory cells, genetic mutations, and epigenetic alterations. Atopic dermatitis is a multifactorial disease with a particularly complicated pathophysiology. Discoveries to date may be considered the tip of the iceberg, and the increasing number of studies in this field indicate that there are many points to be elucidated in AD pathophysiology. In this review, we aimed to illustrate the current understanding of the underlying pathogenic mechanisms in AD, to evaluate available treatment options with a focus on recently discovered therapeutic agents, and to determine the personal, familial, and economic burdens of the disease, which are frequently neglected issues in AD. Currently available therapies only provide transient solutions and cannot fully cure the disease. However, advances in the understanding of the pathogenic mechanisms of the disease have led to the production of new treatment options, while ongoing drug trials also have had promising results.
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Affiliation(s)
- Pınar Gür Çetinkaya
- Division of Pediatric Allergy and Asthma Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Ümit Murat Şahiner
- Division of Pediatric Allergy and Asthma Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
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26
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Basso L, Serhan N, Tauber M, Gaudenzio N. Peripheral neurons: Master regulators of skin and mucosal immune response. Eur J Immunol 2019; 49:1984-1997. [DOI: 10.1002/eji.201848027] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 06/06/2019] [Accepted: 07/17/2019] [Indexed: 12/27/2022]
Affiliation(s)
- Lilian Basso
- Unité de Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056, INSERM Université de Toulouse Toulouse France
| | - Nadine Serhan
- Unité de Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056, INSERM Université de Toulouse Toulouse France
| | - Marie Tauber
- Unité de Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056, INSERM Université de Toulouse Toulouse France
| | - Nicolas Gaudenzio
- Unité de Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056, INSERM Université de Toulouse Toulouse France
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27
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Prostaglandin E 2 (PGE 2)-EP2 signaling negatively regulates murine atopic dermatitis-like skin inflammation by suppressing thymic stromal lymphopoietin expression. J Allergy Clin Immunol 2019; 144:1265-1273.e9. [PMID: 31301371 DOI: 10.1016/j.jaci.2019.06.036] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 06/08/2019] [Accepted: 06/25/2019] [Indexed: 01/23/2023]
Abstract
BACKGROUND Atopic dermatitis (AD) is a common and chronic inflammatory skin disease of type 2 immunity. Keratinocyte-derived cytokines, including thymic stromal lymphopoietin (TSLP) and IL-33, are considered to induce the development of AD. Production of prostanoids, a family of lipid mediators, is increased in AD lesions. However, their physiologic functions remain to be clarified. OBJECTIVES We sought to elucidate the functions of prostanoids in the development of AD. METHODS The roles of prostanoids were investigated in a mouse model of AD induced by repeated application of hapten and PAM212, a keratinocyte cell line. RESULTS Application of indomethacin, which blocks prostanoid synthesis, leads to enhanced TSLP and IL-33 production in the skin, increased serum IgE levels, and exacerbation of skin inflammation in this AD model. The skin inflammation was attenuated in TSLP receptor-deficient mice but not in IL-33-deficient mice, and the indomethacin-enhanced type 2 immune responses were abolished in TSLP receptor-deficient mice. Indomethacin increased protease-activated receptor 2-mediated TSLP production in keratinocytes in vitro, and prostaglandin E2 reversed the increase in TSLP levels through its receptor, the prostaglandin E2 receptor (EP2), by downregulating surface expression of protease-activated receptor 2. Administration of an EP2 agonist canceled indomethacin-enhanced TSLP production and type 2 immune responses in the skin, whereas an EP2 antagonist caused an enhancement of TSLP production and type 2 immune responses in the skin. CONCLUSION Prostaglandin E2-EP2 signaling negatively regulates murine AD-like skin inflammation by suppressing TSLP expression.
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28
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Rahrig S, Dettmann JM, Brauns B, Lorenz VN, Buhl T, Kezic S, Elias PM, Weidinger S, Mempel M, Schön MP, Braun A. Transient epidermal barrier deficiency and lowered allergic threshold in filaggrin-hornerin (FlgHrnr -/- ) double-deficient mice. Allergy 2019; 74:1327-1339. [PMID: 30828807 DOI: 10.1111/all.13756] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 12/19/2018] [Accepted: 01/09/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND Filaggrin (Flg) and hornerin (Hrnr) share similar structural and functional features. Both proteins have been implicated as essential proteins for skin barrier maintenance. Loss-of-function mutations of these genes constitute a risk factor for atopic dermatitis and eczema-related asthma. Furthermore, both FLG and HRNR protein levels are downregulated in patients with atopic dermatitis. Thus, mice deficient for Flg and Hrnr provide a novel model to study skin barrier impairment and the susceptibility for cutaneous inflammation. METHODS By using appropriate targeting vectors and breeding strategies, we established a homozygous FlgHrnr double-deficient (FlgHrnr-/- ) mouse model lacking both genes including the intergenomic sequence. RESULTS Neonates appeared normal, but developed a transient scaly phenotype with overall flaky appearance, but no overt skin phenotype in adulthood, thereby reflecting a subclinical barrier defect seen in humans. Structurally, FlgHrnr-/- mice displayed a markedly reduced granular layer and a condensed cornified layer. Functionally, FlgHrnr-/- mice showed permeability abnormalities and metabolic aberrations regarding the production of natural moisturizing factors (NMFs) in the stratum corneum. Surprisingly, although the immune system revealed no aberrations under steady-state conditions, FlgHrnr-/- mice are predisposed to mount an allergic contact dermatitis, especially at hapten threshold levels eliciting allergic reactions. CONCLUSIONS Together, our FlgHrnr-/- mouse model nicely reflects the epicutaneous sensitization susceptibilities and inflammatory reactions to environmental insults in humans with impaired skin barrier functions.
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Affiliation(s)
- Sebastian Rahrig
- Department of Dermatology, Venereology, and Allergology University Medical Center, Georg August University Göttingen Germany
| | - Judith M. Dettmann
- Department of Dermatology, Venereology, and Allergology University Medical Center, Georg August University Göttingen Germany
| | - Birka Brauns
- Department of Dermatology and Venereology University Medical Center Rostock Germany
| | - Verena N. Lorenz
- Department of Dermatology, Venereology, and Allergology University Medical Center, Georg August University Göttingen Germany
| | - Timo Buhl
- Department of Dermatology, Venereology, and Allergology University Medical Center, Georg August University Göttingen Germany
| | - Sanja Kezic
- Academic Medical Center Coronel Institute of Occupational Health Amsterdam the Netherlands
| | - Peter M. Elias
- Department of Dermatology University of California San Francisco California
| | - Stephan Weidinger
- Department of Dermatology, Venereology and Allergy University Hospital Schleswig‐Holstein Kiel Germany
| | - Martin Mempel
- Department of Dermatology, Venereology, and Allergology University Medical Center, Georg August University Göttingen Germany
- Lower Saxony Institute of Occupational Dermatology University Medical Center Göttingen and University of Osnabrück Göttingen Germany
| | - Michael P. Schön
- Department of Dermatology, Venereology, and Allergology University Medical Center, Georg August University Göttingen Germany
- Lower Saxony Institute of Occupational Dermatology University Medical Center Göttingen and University of Osnabrück Göttingen Germany
| | - Andrea Braun
- Department of Dermatology, Venereology, and Allergology University Medical Center, Georg August University Göttingen Germany
- Lower Saxony Institute of Occupational Dermatology University Medical Center Göttingen and University of Osnabrück Göttingen Germany
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29
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Sakai T, Aoki C, Mori Y, Yamate T, Matsuda-Hirose H, Hatano Y. Site-Specific Microarray Evaluation of Spontaneous Dermatitis in Flaky Tail Mice. J Invest Dermatol 2019; 139:2554-2557.e5. [PMID: 31226263 DOI: 10.1016/j.jid.2019.04.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 04/15/2019] [Accepted: 04/18/2019] [Indexed: 10/26/2022]
Affiliation(s)
- Takashi Sakai
- Department of Dermatology, Faculty of Medicine, Oita University, Oita, Japan.
| | - Chinatsu Aoki
- Medical students in Faculty of Medicine, Oita University, Oita, Japan
| | - Yasuko Mori
- Medical students in Faculty of Medicine, Oita University, Oita, Japan
| | - Tomoko Yamate
- Department of Dermatology, Faculty of Medicine, Oita University, Oita, Japan
| | | | - Yutaka Hatano
- Department of Dermatology, Faculty of Medicine, Oita University, Oita, Japan
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30
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Henehan M, De Benedetto A. Update on protease‐activated receptor 2 in cutaneous barrier, differentiation, tumorigenesis and pigmentation, and its role in related dermatologic diseases. Exp Dermatol 2019; 28:877-885. [DOI: 10.1111/exd.13936] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 03/03/2019] [Accepted: 03/18/2019] [Indexed: 12/20/2022]
Affiliation(s)
- Mason Henehan
- Department of Dermatology College of Medicine University of Florida Gainesville Florida
| | - Anna De Benedetto
- Department of Dermatology College of Medicine University of Florida Gainesville Florida
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31
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Nguyen T, Castex-Rizzi N, Redoulès D. Activités immunomodulatrice, anti-inflammatoire, antiprurigineuse et tolérogénique induites par I-modulia ® , un extrait issu de culture d’ Aquaphilus dolomiae , dans les modèles pharmacologiques de dermatite atopique. Ann Dermatol Venereol 2019; 144 Suppl 1:S42-S49. [PMID: 29221590 DOI: 10.1016/s0151-9638(17)31042-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Atopic dermatitis (AD) is an inflammatory and pruritic dermatosis of multifactorial origin. Topical steroids are the first line treatment for severe AD however alternatives treatment are increasingly needed. A biological concentrate was elaborated from culture of an Avène aquatic microflora isolate namely Aquaphilus dolomiae. Numerous extracts were evaluated in relevant AD in vitro models with human keratinocytes. Among these extracts, a particular one I-modulia® was found to be remarkable in terms of pharmacological activities: innate immunity modulating by agonizing Toll like receptor (TLR)2, TLR4 and TLR5, induction of anti-microbial peptides, inhibition of cytokines characteristics of T helper (Th)1, Th2 and Th17 responses, inhibition of Protease-activated-receptor (PAR) 2 and Thymic-stromal-lymphopoeitin (TSLP) both being known to be upregulated in pruritus. Additionally, when human dendritic cells (DC) were stimulated in vitro by Staphylococcus aureus secretomes from AD children lesions, I-modulia® was capable to induce IL-10 secretion to activate regular T lymphocytes and rendered DC tolerogenic. I-modulia®, extract of biotech origin incorporated in emollient, displays anti-inflammatory, anti-pruritus activities, restores homeostasis immune and ameliorates AD in young infant.
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Affiliation(s)
- T Nguyen
- Pierre Fabre Dermo-Cosmétique, Centre de recherche & développement Pierre Fabre, 3, avenue Hubert-Curien, 31035 Toulouse cedex, France.
| | - N Castex-Rizzi
- Pierre Fabre Dermo-Cosmétique, Centre de recherche & développement Pierre Fabre, 3, avenue Hubert-Curien, 31035 Toulouse cedex, France
| | - D Redoulès
- Pierre Fabre Dermo-Cosmétique, Centre de recherche & développement Pierre Fabre, 3, avenue Hubert-Curien, 31035 Toulouse cedex, France
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32
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Kim HJ, Lee SH, Jeong S, Hong SJ. Protease-Activated Receptors 2-Antagonist Suppresses Asthma by Inhibiting Reactive Oxygen Species-Thymic Stromal Lymphopoietin Inflammation and Epithelial Tight Junction Degradation. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2019; 11:560-571. [PMID: 31172724 PMCID: PMC6557777 DOI: 10.4168/aair.2019.11.4.560] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 02/10/2019] [Accepted: 02/12/2019] [Indexed: 12/24/2022]
Abstract
Purpose Protease-activated receptor 2 (PAR2) reportedly triggers the immune response in allergic asthma. We aimed to investigate the mechanism on allergic inflammation mediated by PAR2. Methods Human lung epithelial cells (A549 cells) were used for in vitro, and the German cockroach extract (GCE)-induced mouse model was developed for in vivo studies. Results In A549 cells, the levels of reactive oxygen species (ROS) and thymic stromal lymphopoietin (TSLP) were significantly increased by GCE treatment, but were suppressed by PAR2-antagonist (PAR2-ant) or N-acetylcysteine (NAC) treatment. Claudin-1 was degraded by GCE, and was restored by PAR2-ant or NAC in the cells. In the mouse model, the clinical appearance including bronchial hyperresponsiveness, bronchoalveolar lavage fluid analysis and total immunoglobulin E were significantly suppressed by PAR2-ant or NAC. Moreover, TSLP levels in the lung were suppressed by the same treatments in the lung. Claudin-1 was also degraded by GCE, and was restored by PAR2-ant or NAC. Conclusions ROS generation and epidermal tight junction degradation are triggered by protease, followed by the induction of TSLP in allergic asthma. Our findings could suggest that PAR2-ant or anti-oxidants could be considered for allergic diseases as preventive alternatives.
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Affiliation(s)
- Ha Jung Kim
- Department of Internal Medicine, Chonnam National University College of Veterinary Medicine, Gwangju, Korea
| | - Seung Hwa Lee
- Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea
| | | | - Soo Jong Hong
- Department of Pediatrics, Childhood Asthma Atopy Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Environmental Health Center, Asan Medical Center, Seoul, Korea.
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33
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Oh MS, Hong JY, Kim MN, Kwak EJ, Kim SY, Kim EG, Lee KE, Kim YS, Jee HM, Kim SH, Sol IS, Park CO, Kim KW, Sohn MH. Activated Leukocyte Cell Adhesion Molecule Modulates Th2 Immune Response in Atopic Dermatitis. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2019; 11:677-690. [PMID: 31332979 PMCID: PMC6658408 DOI: 10.4168/aair.2019.11.5.677] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 05/05/2019] [Indexed: 12/25/2022]
Abstract
PURPOSE Activated leukocyte cell adhesion molecule (ALCAM), a member of the immunoglobulin superfamily, is highly expressed on dendritic cells. ALCAM and its receptor CD6 are co-stimulatory molecules in the immunological synapse; their interaction is required for T cell activation. While atopic dermatitis (AD) is recognized as a T helper 2 (Th2)-mediated allergic disease, the role of ALCAM in its pathogenesis is unclear. METHODS ALCAM levels were measured in the serum of AD patients and AD-induced murine model by ovalbumin treatment. We next investigated transepidermal water loss, clinical score, Th2-immune responses, skin barrier gene expression and T-cell activation using wild-type (WT) and ALCAM deficiency mice. An oxazolone-induced AD-like model was also established and analyzed using WT- and ALCAM-deficient mice. RESULTS We found that serum ALCAM levels were elevated in pediatric AD patients as well as WT AD mice, whereas Th2-type cytokine production and AD symptoms were suppressed in ALCAM-deficient mice. In addition, CD4⁺ effector T-cell counts in murine skin and skin-draining lymph nodes were lower in ALCAM-deficient mice than in their WT counterparts. ALCAM deficiency was also linked to higher expression of skin barrier genes and number of lamellar bodies. CONCLUSIONS These findings indicate that ALCAM may contribute to AD pathogenesis by meditating a Th2-dominant immune response and disrupting the barrier function of the skin.
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Affiliation(s)
- Mi Seon Oh
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jung Yeon Hong
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Mi Na Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Eun Ji Kwak
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Soo Yeon Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Eun Gyul Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung Eun Lee
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Yun Seon Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Mi Jee
- Department of Pediatrics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Seo Hyeong Kim
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - In Suk Sol
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Chang Ook Park
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung Won Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Myung Hyun Sohn
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
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Gouin O, L'Herondelle K, Buscaglia P, Le Gall-Ianotto C, Philippe R, Legoux N, Mignen O, Buhé V, Leschiera R, Sakka M, Kerfant N, Carré JL, Le Garrec R, Lefeuvre L, Lebonvallet N, Misery L. Major Role for TRPV1 and InsP3R in PAR2-Elicited Inflammatory Mediator Production in Differentiated Human Keratinocytes. J Invest Dermatol 2018; 138:1564-1572. [DOI: 10.1016/j.jid.2018.01.034] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 01/24/2018] [Accepted: 01/28/2018] [Indexed: 11/15/2022]
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Kang J, Song J, Shen S, Li B, Yang X, Chen M. Diisononyl phthalate aggravates allergic dermatitis by activation of NF-kB. Oncotarget 2018; 7:85472-85482. [PMID: 27863430 PMCID: PMC5356750 DOI: 10.18632/oncotarget.13403] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Accepted: 10/27/2016] [Indexed: 01/31/2023] Open
Abstract
Several epidemiological studies have suggested a possible link between exposure to Diisononyl phthalate (DINP) and the development of allergies. These findings remain controversial since there is insufficient scientific evidence to assess the ability of DINP to influence allergic immune responses. In addition, the mechanisms behind DINP-caused allergic diseases have not been fully elucidated. In this study, Balb/c mice were orally exposed to DINP for 3 weeks and were then sensitized with fluorescein isothiocyanate (FITC). We showed that oral exposure to DINP could aggravate allergic-dermatitis-like lesions, indicated by an increase in the number of mast cells, and in increased skin edema in FITC-induced contact hypersensitivity. This deterioration was concomitant with increased total serum immunoglobulin-E and Th2 cytokines. We determined the oxidative damage and the activation of nuclear factor-kb (NF-kB). The data demonstrated that DINP could promote oxidative damage and the activation of NF-kB in the skin. The expression of thymic stromal lymphopoietin and the activation of signal transducer and activator of transcriptions 3, 5 and 6 were enhanced concomitant with exacerbated allergic dermatitis effects and the activation of NF-kB induced by DINP. These effects were alleviated by pyrollidine dithiocarbamate, an inhibitor of NF-kB. The results suggest that oral exposure to DINP aggravated allergic contact dermatitis, which was positively regulated via NF-kB.
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Affiliation(s)
- Jun Kang
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, Hubei, China
| | - Jing Song
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, Hubei, China
| | - Shiping Shen
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, Hubei, China
| | - Baizhan Li
- Key Laboratory of the Three Gorges Reservoir Region's Eco-Environment, Ministry of Education, Chongqing University, Chongqing 400045, China
| | - Xu Yang
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, Hubei, China
| | - Mingqing Chen
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, Hubei, China
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37
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Danby SG, Brown K, Wigley AM, Chittock J, Pyae PK, Flohr C, Cork MJ. The Effect of Water Hardness on Surfactant Deposition after Washing and Subsequent Skin Irritation in Atopic Dermatitis Patients and Healthy Control Subjects. J Invest Dermatol 2018; 138:68-77. [DOI: 10.1016/j.jid.2017.08.037] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 08/10/2017] [Accepted: 08/27/2017] [Indexed: 12/20/2022]
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38
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Li Z, Hu L, Elias PM, Man MQ. Skin care products can aggravate epidermal function: studies in a murine model suggest a pathogenic role in sensitive skin. Contact Dermatitis 2017; 78:151-158. [PMID: 29152821 DOI: 10.1111/cod.12909] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 09/12/2017] [Accepted: 09/17/2017] [Indexed: 11/28/2022]
Abstract
BACKGROUND Sensitive skin is defined as a spectrum of unpleasant sensations in response to a variety of stimuli. However, only some skin care products provoke cutaneous symptoms in individuals with sensitive skin. Hence, it would be useful to identify products that could provoke cutaneous symptoms in individuals with sensitive skin. OBJECTIVE To assess whether vehicles, as well as certain branded skin care products, can alter epidermal function following topical applications to normal mouse skin. METHODS Following topical applications of individual vehicle or skin care product to C57BL/6J mice twice daily for 4 days, transepidermal water loss (TEWL) rates, stratum corneum (SC) hydration and skin surface pH were measured on treated versus untreated mouse skin with an MPA5 device and pH 900 pH meter. RESULTS Our results show that all tested products induced abnormalities in epidermal functions of varying severity, including elevations in TEWL and skin surface pH, and reduced SC hydration. CONCLUSIONS Our results suggest that mice can serve as a predictive model that could be used to evaluate the potential safety of skin care products in humans with sensitive skin.
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Affiliation(s)
- Zhengxiao Li
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China.,Dermatology Service, Veterans Affairs Medical Center, and Department of Dermatology, University of California, San Francisco, CA, USA
| | - Lizhi Hu
- Key Laboratory of Immune Microenvironment and Disease (Ministry of State Education), Immunology Department, Tianjin Medical University, Tianjin, 300070, China
| | - Peter M Elias
- Dermatology Service, Veterans Affairs Medical Center, and Department of Dermatology, University of California, San Francisco, CA, USA
| | - Mao-Qiang Man
- Dermatology Service, Veterans Affairs Medical Center, and Department of Dermatology, University of California, San Francisco, CA, USA
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Zhu Y, Underwood J, Macmillan D, Shariff L, O'Shaughnessy R, Harper JI, Pickard C, Friedmann PS, Healy E, Di WL. Persistent kallikrein 5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity. J Allergy Clin Immunol 2017; 140:1310-1322.e5. [DOI: 10.1016/j.jaci.2017.01.025] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 01/16/2017] [Accepted: 01/30/2017] [Indexed: 11/28/2022]
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Otsuka A, Nomura T, Rerknimitr P, Seidel JA, Honda T, Kabashima K. The interplay between genetic and environmental factors in the pathogenesis of atopic dermatitis. Immunol Rev 2017; 278:246-262. [DOI: 10.1111/imr.12545] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Atsushi Otsuka
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
| | - Takashi Nomura
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
| | - Pawinee Rerknimitr
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
- Division of Dermatology; Department of Medicine; Faculty of Medicine, Allergy and Clinical Immunology Research Group; Chulalongkorn University; Bangkok Thailand
| | - Judith A. Seidel
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
| | - Tetsuya Honda
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
| | - Kenji Kabashima
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
- Singapore Immunology Network (SIgN) and Institute of Medical Biology; Agency for Science, Technology and Research (A*STAR); Biopolis; Singapore
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41
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Deckers J, De Bosscher K, Lambrecht BN, Hammad H. Interplay between barrier epithelial cells and dendritic cells in allergic sensitization through the lung and the skin. Immunol Rev 2017; 278:131-144. [DOI: 10.1111/imr.12542] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Julie Deckers
- Department of Internal Medicine; Ghent University; Ghent Belgium
- Laboratory of Immunoregulation and Mucosal Immunology; VIB Center for Inflammation Research; Ghent Belgium
- Department of Biochemistry; Ghent University; Ghent Belgium
- Receptor Research Laboratories; Nuclear Receptor Lab; VIB Center for Medical Biotechnology; Ghent Belgium
| | - Karolien De Bosscher
- Department of Biochemistry; Ghent University; Ghent Belgium
- Receptor Research Laboratories; Nuclear Receptor Lab; VIB Center for Medical Biotechnology; Ghent Belgium
| | - Bart N Lambrecht
- Department of Internal Medicine; Ghent University; Ghent Belgium
- Laboratory of Immunoregulation and Mucosal Immunology; VIB Center for Inflammation Research; Ghent Belgium
- Department of Pulmonary Medicine; Erasmus University Medical Center; Rotterdam The Netherlands
| | - Hamida Hammad
- Department of Internal Medicine; Ghent University; Ghent Belgium
- Laboratory of Immunoregulation and Mucosal Immunology; VIB Center for Inflammation Research; Ghent Belgium
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Yin H, Tian Y, Luo R, Deng Y. Thymic stromal lymphopoietin is expressed in human corneal stromal cells and secreted upon protease-activated receptor 1 activation. IUBMB Life 2017. [PMID: 28631887 DOI: 10.1002/iub.1644] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- Hongbo Yin
- Department of Ophthalmology; West China Hospital, Sichuan University; Chengdu Sichuan People's Republic of China
| | - Yan Tian
- Department of Ophthalmology; West China Hospital, Sichuan University; Chengdu Sichuan People's Republic of China
| | - Rongying Luo
- Department of Ophthalmology; West China Hospital, Sichuan University; Chengdu Sichuan People's Republic of China
| | - Yingping Deng
- Department of Ophthalmology; West China Hospital, Sichuan University; Chengdu Sichuan People's Republic of China
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Rerknimitr P, Otsuka A, Nakashima C, Kabashima K. The etiopathogenesis of atopic dermatitis: barrier disruption, immunological derangement, and pruritus. Inflamm Regen 2017; 37:14. [PMID: 29259713 PMCID: PMC5725646 DOI: 10.1186/s41232-017-0044-7] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 04/12/2017] [Indexed: 02/07/2023] Open
Abstract
Atopic dermatitis (AD) is a common chronic skin inflammatory disorder characterized by recurrent eczema accompanied by an intractable itch that leads to an impaired quality of life. Extensive recent studies have shed light on the multifaceted pathogenesis of the disease. The complex interplay among skin barrier deficiency, immunological derangement, and pruritus contributes to the development, progression, and chronicity of the disease. Abnormalities in filaggrin, other stratum corneum constituents, and tight junctions induce and/or promote skin inflammation. This inflammation, in turn, can further deteriorate the barrier function by downregulating a myriad of essential barrier-maintaining molecules. Pruritus in AD, which may be due to hyperinnervation of the epidermis, increases pruritogens, and central sensitization compromises the skin integrity and promotes inflammation. There are unmet needs in the treatment of AD. Based on the detailed evidence available to date, certain disease mechanisms can be chosen as treatment targets. Numerous clinical trials of biological agents are currently being conducted and are expected to provide treatments for patients suffering from AD in the future. This review summarizes the etiopathogenesis of the disease and provides a rationale for choosing the novel targeted therapy that will be available in the future.
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Affiliation(s)
- Pawinee Rerknimitr
- Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawara, Sakyo, Kyoto, 606-8507 Japan.,Division of Dermatology, Department of Medicine, Faculty of Medicine, Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand
| | - Atsushi Otsuka
- Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawara, Sakyo, Kyoto, 606-8507 Japan
| | - Chisa Nakashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawara, Sakyo, Kyoto, 606-8507 Japan
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawara, Sakyo, Kyoto, 606-8507 Japan.,Singapore Immunology Network (SIgN) and Institute of Medical Biology, Agency for Science, Technology and Research (ASTAR), Biopolis, Singapore
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Elias MS, Long HA, Newman CF, Wilson PA, West A, McGill PJ, Wu KC, Donaldson MJ, Reynolds NJ. Proteomic analysis of filaggrin deficiency identifies molecular signatures characteristic of atopic eczema. J Allergy Clin Immunol 2017; 140:1299-1309. [PMID: 28479159 PMCID: PMC5667587 DOI: 10.1016/j.jaci.2017.01.039] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 12/22/2016] [Accepted: 01/20/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND Atopic eczema (AE) is characterized by skin barrier and immune dysfunction. Null mutations in filaggrin (FLG), a key epidermal barrier protein, strongly predispose to AE; however, the precise role of FLG deficiency in AE pathogenesis remains incompletely understood. OBJECTIVES We sought to identify global proteomic changes downstream of FLG deficiency in human epidermal living skin-equivalent (LSE) models and validate findings in skin of patients with AE. METHODS Differentially expressed proteins from paired control (nontargeting control short hairpin RNA [shNT]) and FLG knockdown (FLG knockdown short hairpin RNA [shFLG]) LSEs were identified by means of proteomic analysis (liquid chromatography-mass spectrometry) and Ingenuity Pathway Analysis. Expression of key targets was validated in independent LSE samples (quantitative RT-PCR and Western blotting) and in normal and AE skin biopsy specimens (immunofluorescence). RESULTS Proteomic analysis identified 17 (P ≤ .05) differentially expressed proteins after FLG knockdown, including kallikrein-7 (KLK7; 2.2-fold), cyclophilin A (PPIA; 0.9-fold), and cofilin-1 (CFL1, 1.3-fold). Differential protein expression was confirmed in shNT/shFLG LSEs; however, only KLK7 was transcriptionally dysregulated. Molecular pathways overrepresented after FLG knockdown included inflammation, protease activity, cell structure, and stress. Furthermore, KLK7 (1.8-fold) and PPIA (0.65-fold) proteins were differentially expressed in lesional biopsy specimens from patients with AE relative to normal skin. CONCLUSIONS For the first time, we show that loss of FLG in the absence of inflammation is sufficient to alter the expression level of proteins relevant to the pathogenesis of AE. These include proteins regulating inflammatory, proteolytic, and cytoskeletal functions. We identify PPIA as a novel protein with levels that are decreased in clinically active AE skin and show that the characteristic upregulation of KLK7 expression in patients with AE occurs downstream of FLG loss. Importantly, we highlight disconnect between the epidermal proteome and transcriptome, emphasizing the utility of global proteomic studies.
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Affiliation(s)
- Martina S Elias
- Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Heather A Long
- Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Stiefel, a GlaxoSmithKline company, Stevenage, United Kingdom
| | | | | | - Andrew West
- GlaxoSmithKline R&D, Stevenage, United Kingdom
| | | | - Keith C Wu
- Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | | | - Nick J Reynolds
- Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom.
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TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization. Protein Cell 2017; 8:644-661. [PMID: 28364279 PMCID: PMC5563280 DOI: 10.1007/s13238-017-0395-5] [Citation(s) in RCA: 259] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 02/28/2017] [Indexed: 12/19/2022] Open
Abstract
Cutaneous neurogenic inflammation (CNI) is inflammation that is induced (or enhanced) in the skin by the release of neuropeptides from sensory nerve endings. Clinical manifestations are mainly sensory and vascular disorders such as pruritus and erythema. Transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) are non-selective cation channels known to specifically participate in pain and CNI. Both TRPV1 and TRPA1 are co-expressed in a large subset of sensory nerves, where they integrate numerous noxious stimuli. It is now clear that the expression of both channels also extends far beyond the sensory nerves in the skin, occuring also in keratinocytes, mast cells, dendritic cells, and endothelial cells. In these non-neuronal cells, TRPV1 and TRPA1 also act as nociceptive sensors and potentiate the inflammatory process. This review discusses the role of TRPV1 and TRPA1 in the modulation of inflammatory genes that leads to or maintains CNI in sensory neurons and non-neuronal skin cells. In addition, this review provides a summary of current research on the intracellular sensitization pathways of both TRP channels by other endogenous inflammatory mediators that promote the self-maintenance of CNI.
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Shen S, Li J, You H, Wu Z, Wu Y, Zhao Y, Zhu Y, Guo Q, Li X, Li R, Ma P, Yang X, Chen M. Oral exposure to diisodecyl phthalate aggravates allergic dermatitis by oxidative stress and enhancement of thymic stromal lymphopoietin. Food Chem Toxicol 2017; 99:60-69. [DOI: 10.1016/j.fct.2016.11.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 09/27/2016] [Accepted: 11/17/2016] [Indexed: 11/15/2022]
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Aries MF, Hernandez-Pigeon H, Vaissière C, Delga H, Caruana A, Lévêque M, Bourrain M, Ravard Helffer K, Chol B, Nguyen T, Bessou-Touya S, Castex-Rizzi N. Anti-inflammatory and immunomodulatory effects of Aquaphilus dolomiae extract on in vitro models. Clin Cosmet Investig Dermatol 2016; 9:421-434. [PMID: 27877060 PMCID: PMC5108493 DOI: 10.2147/ccid.s113180] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background Atopic dermatitis (AD) is a common skin disease characterized by recurrent pruritic inflammatory skin lesions resulting from structural and immune defects of the skin barrier. Previous studies have shown the clinical efficacy of Avène thermal spring water in AD, and a new microorganism, Aquaphilus dolomiae was suspected to contribute to these unique properties. The present study evaluated the anti-inflammatory, antipruritic, and immunomodulatory properties of ES0, an original biological extract of A. dolomiae, in immune and inflammatory cell models in order to assess its potential use in the treatment of AD. Materials and methods An ES0 extract containing periplasmic and membrane proteins, peptides, lipopolysaccharides, and exopolysaccharides was obtained from A. dolomiae. The effects of the extract on pruritus and inflammatory mediators and immune mechanisms were evaluated by using various AD cell models and assays. Results In a keratinocyte model, ES0 inhibited the expression of the inflammatory mediators, thymic stromal lymphopoietin, interleukin (IL)-18, IL-4R, IL-8, monocyte chemoattractant protein-3, macrophage inflammatory protein-3α, and macrophage-derived chemokine and induced the expression of involucrin, which is involved in skin barrier keratinocyte terminal differentiation. In addition, ES0 inhibited protease-activated receptor-2 activation in HaCaT human keratinocytes stimulated by stratum corneum tryptic enzyme and T helper type (Th) 1, Th2, and Th17 cytokine production in Staphylococcal enterotoxin B–stimulated CD4+ lymphocytes. Lastly, ES0 markedly activated innate immunity through toll-like receptor (TLR) 2, TLR4, and TLR5 activation (in recombinant human embryonic kidney 293 cells) and through antimicrobial peptide induction (psoriasin, human beta-defensin-2, and cathelicidin), mainly through TLR5 activation (in normal human keratinocytes). Conclusion Overall, these in vitro results confirm the marked regulatory activity of this A. dolomiae extract on inflammatory and immune responses, which may be of value by virtue of its potential as an adjunctive treatment of AD inflammatory and pruritic lesions.
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Affiliation(s)
- Marie-Françoise Aries
- Pierre Fabre Dermo-Cosmétique, Centre de Recherche & Développement Pierre Fabre, Toulouse
| | | | - Clémence Vaissière
- Pierre Fabre Dermo-Cosmétique, Centre de Recherche & Développement Pierre Fabre, Toulouse
| | - Hélène Delga
- Pierre Fabre Dermo-Cosmétique, Centre de Recherche & Développement Pierre Fabre, Toulouse
| | - Antony Caruana
- Pierre Fabre Dermo-Cosmétique, Centre de Recherche & Développement Pierre Fabre, Toulouse
| | - Marguerite Lévêque
- Pierre Fabre Dermo-Cosmétique, Centre de Recherche & Développement Pierre Fabre, Toulouse
| | - Muriel Bourrain
- Pierre Fabre Dermo-Cosmétique, Centre de Recherche & Développement Pierre Fabre, Toulouse; Sorbonne Universités, UPMC Univ Paris 06, CNRS, Laboratoire de Biodiversité et Biotechnologies Microbiennes (LBBM), Observatoire Océanologique, Banyuls/Mer, France
| | - Katia Ravard Helffer
- Pierre Fabre Dermo-Cosmétique, Centre de Recherche & Développement Pierre Fabre, Toulouse
| | - Bertrand Chol
- Centre d'Immunologie Pierre Fabre, Saint-Julien-en-Genevois, France
| | - Thien Nguyen
- Pierre Fabre Dermo-Cosmétique, Centre de Recherche & Développement Pierre Fabre, Toulouse
| | - Sandrine Bessou-Touya
- Pierre Fabre Dermo-Cosmétique, Centre de Recherche & Développement Pierre Fabre, Toulouse
| | - Nathalie Castex-Rizzi
- Pierre Fabre Dermo-Cosmétique, Centre de Recherche & Développement Pierre Fabre, Toulouse
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Kim HJ, Jeong SK, Hong SJ, Ahrens K, Marsella R. Effects of PAR2 antagonist on inflammatory signals and tight junction expression in protease-activated canine primary epithelial keratinocytes. Exp Dermatol 2016; 26:86-88. [PMID: 27306682 DOI: 10.1111/exd.13121] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/06/2016] [Indexed: 12/01/2022]
Affiliation(s)
- Ha-Jung Kim
- Department of Veterinary Internal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea
| | | | - Soo-Jong Hong
- Department of Pediatrics, Childhood Asthma Atopy Center, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
| | - Kim Ahrens
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
| | - Rosanna Marsella
- Department of Dermatology, College of Medicine, University of Florida, Gainesville, FL, USA
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Lee HJ, Lee NR, Kim BK, Jung M, Kim DH, Moniaga CS, Kabashima K, Choi EH. Acidification of stratum corneum prevents the progression from atopic dermatitis to respiratory allergy. Exp Dermatol 2016; 26:66-72. [DOI: 10.1111/exd.13144] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2016] [Indexed: 12/12/2022]
Affiliation(s)
- Hae-Jin Lee
- Department of Dermatology; Cutaneous Biology Research Institute; Yonsei University College of Medicine; Seoul Korea
| | - Noo Ri Lee
- Department of Dermatology; Yonsei University Wonju College of Medicine; Wonju Korea
| | - Bo-Kyung Kim
- Department of Dermatology; Yonsei University Wonju College of Medicine; Wonju Korea
| | - Minyoung Jung
- Department of Dermatology; Yonsei University Wonju College of Medicine; Wonju Korea
| | - Dong Hye Kim
- Department of Dermatology; Yonsei University Wonju College of Medicine; Wonju Korea
| | - Catharina S. Moniaga
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
| | - Kenji Kabashima
- Department of Dermatology; Kyoto University Graduate School of Medicine; Kyoto Japan
| | - Eung Ho Choi
- Department of Dermatology; Yonsei University Wonju College of Medicine; Wonju Korea
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50
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Lee H, Park JB, Bae HC, Ryu WI, Shin JJ, Son SW. Toluene induces early growth response-1 dependent thymic stromal lymphopoietin expression in human keratinocytes. Mol Cell Toxicol 2016. [DOI: 10.1007/s13273-016-0032-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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