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Redhu D, Kumari V, Franke K, Hartmann K, Worm M, Babina M. TNF-α counters skin inflammation by restraining mast cell-dependent thymic stromal lymphopoietin production. J Allergy Clin Immunol 2025:S0091-6749(25)00369-0. [PMID: 40189158 DOI: 10.1016/j.jaci.2025.03.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 03/10/2025] [Accepted: 03/24/2025] [Indexed: 04/25/2025]
Abstract
BACKGROUND TNF-α is an important proinflammatory cytokine, but its neutralization in the management of inflammatory skin disorders like psoriasis may trigger eczematous skin lesions as an adverse reaction. OBJECTIVES This study aimed to elucidate whether TNF-α may protect from skin inflammation and to identify in detail the underlying mechanisms. METHODS Wild-type, TNF-α-deficient, thymic stromal lymphopoietin (TSLP) receptor-deficient, mast cell (MC)-deficient, TNF-α-TSLP receptor double-deficient, and TNF-α-MC double-deficient mice were subjected to a skin inflammation model and inspected by physical, clinical, histologic, immunohistochemical, and bioanalytic techniques. RESULTS TNF-α deficiency promoted skin inflammation. This was accompanied by MC hyperplasia and potent TSLP production in lesional skin and serum of TNF-α-deficient mice. Specifically, MCs were found to be responsible for inducing high levels of TSLP in the epidermis, compromising barrier function and initiating inflammation. In contrast, the production of immunoglobulins, including IgE, was reduced in mice lacking TNF-α. CONCLUSIONS TNF-α restrains MC-dependent TSLP production and the onset of eczema.
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Affiliation(s)
- Davender Redhu
- Division of Allergy and Immunology, Department of Dermatology, Venerology and Allergy, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Vandana Kumari
- Center of Allergy & Environment (ZAUM), Institute of Allergy Research (IAF), Helmholtz Center Munich, Munich, Germany
| | - Kristin Franke
- Institute of Allergology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, Berlin, Germany
| | - Karin Hartmann
- Division of Allergy, Department of Dermatology, the Department of Clinical Research, and the Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Margitta Worm
- Division of Allergy and Immunology, Department of Dermatology, Venerology and Allergy, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Magda Babina
- Institute of Allergology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, Berlin, Germany.
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2
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Qian X, Tong M, Zhang T, Li Q, Hua M, Zhou N, Zeng W. IL-24 promotes atopic dermatitis-like inflammation through driving MRSA-induced allergic responses. Protein Cell 2025; 16:188-210. [PMID: 38752989 PMCID: PMC11892005 DOI: 10.1093/procel/pwae030] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 04/25/2024] [Indexed: 03/11/2025] Open
Abstract
Atopic dermatitis (AD) is a prevalent inflammatory skin disorder in which patients experience recurrent eczematous lesions and intense itching. The colonization of Staphylococcus aureus (S. aureus) is correlated with the severity of the disease, but its role in AD development remains elusive. Using single-cell RNA sequencing, we uncovered that keratinocytes activate a distinct immune response characterized by induction of Il24 when exposed to methicillin-resistant S. aureus (MRSA). Further experiments using animal models showed that the administration of recombinant IL-24 protein worsened AD-like pathology. Genetic ablation of Il24 or the receptor Il20rb in keratinocytes alleviated allergic inflammation and atopic march. Mechanistically, IL-24 acted through its heterodimeric receptors on keratinocytes and augmented the production of IL-33, which in turn aggravated type 2 immunity and AD-like skin conditions. Overall, these findings establish IL-24 as a critical factor for onset and progression of AD and a compelling therapeutic target.
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Affiliation(s)
- Xinmin Qian
- Institute for Immunology and School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing 100084, China
| | - Meiyi Tong
- Eight-year Medical Doctor Program, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100084, China
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Tianqing Zhang
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Qingqing Li
- Institute for Immunology and School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing 100084, China
| | - Meng Hua
- Institute for Immunology and School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing 100084, China
| | - Nan Zhou
- Institute for Immunology and School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing 100084, China
| | - Wenwen Zeng
- Institute for Immunology and School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing 100084, China
- SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan 030001, China
- Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
- Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing 100084, China
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3
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Yu SE, Olonisakin TF, Moore JA, Chiang S, Lee SE. The Association of TSLP and IL-4 with Patient-Reported Outcome Measures in Chronic Rhinosinusitis with Nasal Polyps. Am J Rhinol Allergy 2025; 39:118-127. [PMID: 39791191 DOI: 10.1177/19458924241311354] [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] [Indexed: 01/12/2025]
Abstract
BACKGROUND Thymic stromal lymphopoietin (TSLP) plays an important role in mediating the type-2-inflammatory response. This study examined how TSLP and interleukin (IL)-4 levels in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) correlated with clinical and postoperative outcomes. METHODS Solid-phase sandwich ELISA was used to analyze TSLP and IL-4 levels in mucus (n = 47), plasma (n = 17), polyp (n = 30), inferior (n = 25), and middle (n = 26) turbinate tissue collected during functional endoscopic sinus surgery (FESS) in CRSwNP patients (n = 76) and controls (n = 11). Inclusion criteria includes patients with medical treatment refractory CRSwNP confirmed by endoscopy or maxillofacial CT. Exclusion criteria include history of immunodeficiency, coagulation disorders, fungal sinusitis, or cystic fibrosis. Levels of TSLP and IL-4 were correlated with SNOT-22, UPSIT, and fractional exhaled nitric oxide (FeNO) using MannWhitney U two-tailed test and linear regression with Spearman correlation coefficient test. RESULTS TSLP is elevated in the inferior turbinates (effect size = 2.695, p = 0.0007) of CRSwNP patients compared to controls. IL-4 is expressed at elevated levels in the inferior (effect size = 3.092, p < 0.0001) and middle turbinates (effect size = 2.041, p = 0.019) compared to controls. Mucus TSLP (r = 0.4013, p = 0.0153) and IL-4 (r = 0.6138, p < 0.0001) positively correlate with preoperative FeNO levels. Lower TSLP in the inferior (r = -0.5179, p = 0.0231) and middle turbinates (r = -0.5075, p = 0.0224) and lower IL-4 in the inferior turbinates (r = -0.5205, p = 0.0223) correlate with a greater improvement in SNOT-22 post-FESS. CONCLUSION TSLP and IL-4 are elevated in patients with CRSwNP and correlated with increased preoperative FeNO levels and decreased sinonasal quality of life benefit after FESS. Expression of TSLP and IL-4 may play a role in guiding postoperative expectations in patients with treatment refractory CRSwNP.
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Affiliation(s)
- Sophie E Yu
- Division of Otolaryngology - Head & Neck Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Tolani F Olonisakin
- Department of Otolaryngology - Head & Neck Surgery, Johns Hopkins Hospital, Baltimore, MD, USA
| | - John A Moore
- Department of Otolaryngology - Head and Neck Surgery, University of Pittsburgh Medical Center, Mercy Hospital, Pittsburgh, PA, USA
| | - Simon Chiang
- Division of Otolaryngology - Head & Neck Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Stella E Lee
- Division of Otolaryngology - Head & Neck Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Center for Surgery and Public Health, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA
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Moreno-Jiménez E, Morgado N, Gómez-García M, Sanz C, Gil-Melcón M, Isidoro-García M, Dávila I, García-Sánchez A. TSLP and TSLPR Expression Levels in Peripheral Blood as Potential Biomarkers in Patients with Chronic Rhinosinusitis with Nasal Polyps. Int J Mol Sci 2025; 26:1227. [PMID: 39940994 PMCID: PMC11818291 DOI: 10.3390/ijms26031227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/28/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
TSLP is an alarmin released upon activation of epithelia in response to various external stimuli and is involved in type 2 cytokine-mediated pathological disorders. The formation of a high-affinity heterodimeric receptor complex, comprising the thymic stromal lymphopoietin receptor (TSLPR) chain and IL-7Rα, is required for signaling. This study investigated whether TSLP and TSLPR expression in peripheral blood or nasal polyps could provide a valuable approach for the molecular phenotyping of patients with chronic rhinosinusitis with nasal polyps (CRSwNP). The study population comprised 156 unrelated Caucasian individuals, including 45 controls and 111 patients with CRSwNP. Quantitative PCR analysis of TSLP and TSLPR was performed on the population study's peripheral blood and nasal biopsy. The data were analyzed for potential associations, and possible use as a biomarker was studied. Significant differences were observed in TSLP and TSLPR blood expression between the control group and patients. Similarly, the expression of TSLP observed in biopsy samples was statistically significantly elevated in the polyp tissue of the patient compared with healthy controls. The combination of TSLP and TSLPR expression testing with peripheral blood eosinophils represents a more specific biomarker in patients exhibiting low eosinophil values. Further investigation of TSLP/TSLPR mRNA levels in peripheral blood may yield new minimally invasive biomarkers.
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Affiliation(s)
- Emma Moreno-Jiménez
- Instituto de Investigación Biomédica de Salamanca, 37007 Salamanca, Spain; (E.M.-J.); (N.M.); (M.G.-G.); (M.I.-G.); (I.D.); (A.G.-S.)
- Microbiology and Genetics Department, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Natalia Morgado
- Instituto de Investigación Biomédica de Salamanca, 37007 Salamanca, Spain; (E.M.-J.); (N.M.); (M.G.-G.); (M.I.-G.); (I.D.); (A.G.-S.)
- Microbiology and Genetics Department, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Manuel Gómez-García
- Instituto de Investigación Biomédica de Salamanca, 37007 Salamanca, Spain; (E.M.-J.); (N.M.); (M.G.-G.); (M.I.-G.); (I.D.); (A.G.-S.)
- Clinical Biochemistry Department, Hospital Universitario de Salamanca, 37007 Salamanca, Spain
| | - Catalina Sanz
- Instituto de Investigación Biomédica de Salamanca, 37007 Salamanca, Spain; (E.M.-J.); (N.M.); (M.G.-G.); (M.I.-G.); (I.D.); (A.G.-S.)
- Microbiology and Genetics Department, Universidad de Salamanca, 37007 Salamanca, Spain
- Instituto de Salud Carlos III, Red de Enfermedades Inflamatorias—RICORS, 28029 Madrid, Spain
| | - María Gil-Melcón
- Otorhinolaryngology and Head and Neck Surgery Department, Hospital Universitario de Salamanca, 37007 Salamanca, Spain;
| | - María Isidoro-García
- Instituto de Investigación Biomédica de Salamanca, 37007 Salamanca, Spain; (E.M.-J.); (N.M.); (M.G.-G.); (M.I.-G.); (I.D.); (A.G.-S.)
- Clinical Biochemistry Department, Hospital Universitario de Salamanca, 37007 Salamanca, Spain
- Instituto de Salud Carlos III, Red de Enfermedades Inflamatorias—RICORS, 28029 Madrid, Spain
- Medicine Department, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Ignacio Dávila
- Instituto de Investigación Biomédica de Salamanca, 37007 Salamanca, Spain; (E.M.-J.); (N.M.); (M.G.-G.); (M.I.-G.); (I.D.); (A.G.-S.)
- Instituto de Salud Carlos III, Red de Enfermedades Inflamatorias—RICORS, 28029 Madrid, Spain
- Biomedical and Diagnostics Sciences Department, Universidad de Salamanca, 37007 Salamanca, Spain
- Allergy Department, Hospital Universitario de Salamanca, 37007 Salamanca, Spain
| | - Asunción García-Sánchez
- Instituto de Investigación Biomédica de Salamanca, 37007 Salamanca, Spain; (E.M.-J.); (N.M.); (M.G.-G.); (M.I.-G.); (I.D.); (A.G.-S.)
- Instituto de Salud Carlos III, Red de Enfermedades Inflamatorias—RICORS, 28029 Madrid, Spain
- Biomedical and Diagnostics Sciences Department, Universidad de Salamanca, 37007 Salamanca, Spain
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Gurram RK, Li P, Oh J, Chen X, Spolski R, Yao X, Lin JX, Roy S, Liao MJ, Liu C, Yu ZX, Levine SJ, Zhu J, Leonard WJ. TSLP acts on regulatory T cells to maintain their identity and limit allergic inflammation. Sci Immunol 2025; 10:eadk0073. [PMID: 39792638 DOI: 10.1126/sciimmunol.adk0073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 07/08/2024] [Accepted: 12/12/2024] [Indexed: 01/30/2025]
Abstract
Thymic stromal lymphopoietin (TSLP) is a type I cytokine that promotes allergic responses and mediates type 2 immunity. A balance between effector T cells (Teffs), which drive the immune response, and regulatory T cells (Tregs), which suppress the response, is required for proper immune homeostasis. Here, we report that TSLP differentially acts on Teffs versus Tregs to balance type 2 immunity. As expected, deletion of TSLP receptor (TSLPR) on all T cells (Cd4CreCrlf2fl/fl mice) resulted in lower numbers of T helper 2 (TH2) cells and diminished ovalbumin-induced airway inflammation, but selective deletion of TSLPR on Tregs (Foxp3YFP-Cre/YCrlf2fl/fl mice) resulted in increased interleukin-5 (IL-5)- and IL-13-secreting TH2 cells and lung eosinophilia. Moreover, TSLP augmented the expression of factors that stabilize Tregs. During type 2 immune responses, TSLPR-deficient Tregs acquired TH2-like properties, with augmented GATA3 expression and secretion of IL-13. TSLP not only is a driver of TH2 effector cells but also acts in a negative feedback loop, thus promoting the ability of Tregs to limit allergic inflammation.
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Affiliation(s)
- Rama K Gurram
- Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Peng Li
- Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Jangsuk Oh
- Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Xi Chen
- Molecular and Cellular Immunoregulation Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
| | - Rosanne Spolski
- Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Xianglan Yao
- Critical Care Medicine and Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892-1674, USA
| | - Jian-Xin Lin
- Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Suyasha Roy
- Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Matthew J Liao
- Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Chengyu Liu
- Transgenic Core, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA
| | - Zu-Xi Yu
- Pathology Core, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA
| | - Stewart J Levine
- Critical Care Medicine and Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892-1674, USA
| | - Jinfang Zhu
- Molecular and Cellular Immunoregulation Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
| | - Warren J Leonard
- Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
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6
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Schettini N, Pacetti L, Corazza M, Borghi A. The Role of OX40-OX40L Axis in the Pathogenesis of Atopic Dermatitis. Dermatitis 2025; 36:28-36. [PMID: 38700255 DOI: 10.1089/derm.2024.0058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
OX40 is a co-stimulatory immune checkpoint molecule that promotes the activation and the effector function of T lymphocytes through interaction with its ligand (OX40L) on antigen-presenting cells. OX40-OX40L axis plays a crucial role in Th1 and Th2 cell expansion, particularly during the late phases or long-lasting response. Atopic dermatitis is characterized by an immune dysregulation of Th2 activity and by an overproduction of proinflammatory cytokines such as interleukin (IL)-4 and IL-13. Other molecules involved in its pathogenesis include thymic stromal lymphopoietin, IL-33, and IL-25, which contribute to the promotion of OX40L expression on dendritic cells. Lesional skin in atopic dermatitis exhibits a higher level of OX40L+-presenting cells compared with other dermatologic diseases or normal skin. Recent clinical trials using antagonizing anti-OX40 or anti-OX40L antibodies have shown symptom improvement and cutaneous manifestation alleviation in patients with atopic dermatitis. These findings suggest the relevance of the OX40-OX40L axis in atopic dermatitis pathogenesis.
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Affiliation(s)
- Natale Schettini
- From the Section of Dermatology and Infectious Diseases, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Lucrezia Pacetti
- From the Section of Dermatology and Infectious Diseases, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Monica Corazza
- From the Section of Dermatology and Infectious Diseases, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Alessandro Borghi
- From the Section of Dermatology and Infectious Diseases, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
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7
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Kang YM, Kim HM, Lee J, Baek JS, Lee M, An HJ. Indole-3-carbinol alleviates allergic skin inflammation via periostin/thymic stromal lymphopoietin suppression in atopic dermatitis. Chin Med 2024; 19:177. [PMID: 39722037 DOI: 10.1186/s13020-024-01042-5] [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: 03/11/2024] [Accepted: 11/27/2024] [Indexed: 12/28/2024] Open
Abstract
BACKGROUND Atopic dermatitis (AD) is a chronic multifactorial inflammatory skin disorder with a complex etiology. Despite its increasing prevalence, treatment of AD is still limited. Indole-3-carbinol (I3C) is found in cruciferous vegetables and is formed when these vegetables are cut, chewed, or cooked; it exerts diverse pharmacological activities. METHODS HaCaT keratinocytes stimulated with tumor necrosis factor-α and interferon-γ mixture and NC/Nga mice stimulated with 2,4-dinitrochlorobenzen (DNCB) were used for AD models, in vitro and in vivo, respectively. RESULTS The results showed that I3C reduced the expression of pro-inflammatory cytokines, thymic stromal lymphopoietin (TSLP), and periostin in in vitro model. Oral administration of I3C alleviated AD-like skin inflammatory symptoms, including serum IgE levels, epidermal thickening, inflammatory cell infiltration, transepidermal water loss, and scratching behavior. Moreover, I3C decreased the expression of TSLP and periostin and recovered the expression of skin barrier proteins by regulating Aryl Hydrocarbon Receptor and inhibiting the mitogen-activated protein kinase and nuclear factor-κB pathways in the skin of DNCB-induced AD mice. CONCLUSIONS I3C is suggested as a potential therapeutic alternative for the treatment of AD by repressing allergic inflammatory pathways.
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Affiliation(s)
- Yun-Mi Kang
- Department of Herbology, College of Korean Medicine, Sangji University, Wonju, Gangwon-Do, 26339, Republic of Korea
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), 70 Cheomdan-Ro, Dong-Gu, Daegu, 41062, Republic of Korea
| | - Hye-Min Kim
- Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea
- Department of Herbology, College of Korean Medicine, Sangji University, Wonju, Gangwon-Do, 26339, Republic of Korea
| | - Junho Lee
- Department of Bio-Health Convergence, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Jong-Suep Baek
- Department of Bio-Health Convergence, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Minho Lee
- Department of Life Science, Dongguk University-Seoul, Ilsandong-Gu, Goyang-Si, 10326, Gyeonggi-do, Republic of Korea.
| | - Hyo-Jin An
- Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea.
- Department of Integrated Drug Development and Natural Products, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea.
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8
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Tang Y, Zhou Y, Ren J, Wang Y, Li X, Qi M, Yang Y, Zhu C, Wang C, Ma Y, Tang Z, Yu G. TRPV4-β-catenin axis is a novel therapeutic target for dry skin-induced chronic itch. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167491. [PMID: 39218273 DOI: 10.1016/j.bbadis.2024.167491] [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: 01/19/2024] [Revised: 08/13/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024]
Abstract
Dry skin induced chronic pruritus is an increasingly common and debilitating problem, especially in the elderly. Although keratinocytes play important roles in innate and adaptive immunity and keratinocyte proliferation is a key feature of dry skin induced chronic pruritus, the exact contribution of keratinocytes to the pathogenesis of dry skin induced chronic pruritus is poorly understood. In this study, we generated the acetone-ether-water induced dry skin model in mice and found that epidermal hyperplasia induced by this model is partly dependent on the β-catenin signaling pathway. XAV939, an antagonist of β-catenin signaling pathway, inhibited epidermal hyperplasia in dry skin model mice. Importantly, dry skin induced chronic pruritus also dramatically reduced in XAV939 treated mice. Moreover, acetone-ether-water treatment-induced epidermal hyperplasia and chronic itch were decreased in Trpv4-/- mice. In vitro, XAV939 inhibited hypo-osmotic stress induced proliferation of HaCaT cells, and hypo-osmotic stress induced proliferation of in HaCaT cells and primary cultured keratinocytes were also significantly reduced by blocking TRPV4 function. Finally, thymic stromal lymphopoietin release was examined both in vivo and in vitro, which was significantly inhibited by XAV939 treatment and Trpv4 deficiency, and anti-TSLP antibody treatment significantly decreased AEW-induced scratching behavior. Overall, our study revealed a unique ability of TRPV4 expressing keratinocytes in the skin, which critically mediated dry skin induced epidermal hyperplasia and chronic pruritus, thus provided novel insights into the development of therapies for chronic pruritus in the elderly.
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Affiliation(s)
- Ye Tang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, China; Key Laboratory for Chinese Medicine of Prevention and Treatment in Neurological Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Yuan Zhou
- Key Laboratory for Chinese Medicine of Prevention and Treatment in Neurological Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Jiahui Ren
- Key Laboratory for Chinese Medicine of Prevention and Treatment in Neurological Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Yin Wang
- Key Laboratory for Chinese Medicine of Prevention and Treatment in Neurological Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Xue Li
- Key Laboratory for Chinese Medicine of Prevention and Treatment in Neurological Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Mingxin Qi
- Key Laboratory for Chinese Medicine of Prevention and Treatment in Neurological Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Yan Yang
- Key Laboratory for Chinese Medicine of Prevention and Treatment in Neurological Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Chan Zhu
- Key Laboratory for Chinese Medicine of Prevention and Treatment in Neurological Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Changming Wang
- Key Laboratory for Chinese Medicine of Prevention and Treatment in Neurological Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Yuxiang Ma
- School of Life Science, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
| | - Zongxiang Tang
- Key Laboratory for Chinese Medicine of Prevention and Treatment in Neurological Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
| | - Guang Yu
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, China; Key Laboratory for Chinese Medicine of Prevention and Treatment in Neurological Diseases, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
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9
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Tang X, Li M. The role of the skin in the atopic march. Int Immunol 2024; 36:567-577. [PMID: 39271155 DOI: 10.1093/intimm/dxae053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 09/12/2024] [Indexed: 09/15/2024] Open
Abstract
Atopic diseases, including atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis (AR) are closely related to inflammatory diseases involving different body sites (i.e. the skin, airway, and digestive tract) with characteristic features including specific IgE to allergens (so-called "atopy") and Th2 cell-mediated inflammation. It has been recognized that AD often precedes the development of other atopic diseases. The progression from AD during infancy to FA or asthma/AR in later childhood is referred to as the "atopic march" (AM). Clinical, genetic, and experimental studies have provided evidence that allergen sensitization occurring through AD skin could be the origin of the AM. Here, we provide an updated review focusing on the role of the skin in the AM, from genetic mutations and environmental factors associated with epidermal barrier dysfunction in AD and the AM to immunological mechanisms for skin sensitization, particularly recent progress on the function of key cytokines produced by epidermal keratinocytes or by immune cells infiltrating the skin during AD. We also highlight the importance of developing strategies that target AD skin to prevent and attenuate the AM.
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Affiliation(s)
- Xin Tang
- Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, Université de Strasbourg, Illkirch 67404, France
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 40000, People's Republic of China
| | - Mei Li
- Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, Université de Strasbourg, Illkirch 67404, France
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10
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Maskey AR, Mo X, Li XM. Preclinical Models of Atopic Dermatitis Suitable for Mechanistic and Therapeutic Investigations. J Inflamm Res 2024; 17:6955-6970. [PMID: 39372589 PMCID: PMC11456296 DOI: 10.2147/jir.s467327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 08/07/2024] [Indexed: 10/08/2024] Open
Abstract
Atopic dermatitis (AD) is a complex immune-mediated abnormality of the skin characterized by impaired barrier function, eczematous dermatitis, chronic pruritus and itch. The immunological response in AD is mediated by a Th2-dominated immune response in the early acute phase followed by a Th1/ Th2 mixed immune response in the chronic phase. AD is the first step of the "atopic march" that progresses into food allergy, allergic rhinitis, and asthma. Different models are indispensable for studying AD pathogenesis and for designing pre-clinical studies for therapeutic discovery. They reflect the characteristic morphological features of typical human AD with regard to epidermal thickening, hyperkeratosis, acanthosis, and spongiosis and help understand the immunopathogenesis of the disease with respect to IgE levels and cellular infiltration of eosinophils, mast cells, and lymphocytes. Although it is difficult to replicate all human AD clinical features in a model, several AD in vivo models comprising spontaneous, induced, transgenic, and humanized and in vitro models, including 2D, co-culture, and 3D, have been described previously. However, several questions remain regarding whether these models satisfactorily reflect the complexity of human AD. Therefore, this review comprehensively highlights the diversity of currently available models and provides insights into the selection of suitable models based on research questions. It also summarizes the diverse mechanisms associated with each model, which may be valuable for better study design to test new therapeutic options.
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Affiliation(s)
- Anish R Maskey
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY, 10595, USA
| | - Xian Mo
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY, 10595, USA
- The Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, Guangzhou, People’s Republic of China
| | - Xiu-Min Li
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY, 10595, USA
- Department of Otolaryngology, New York Medical College, Valhalla, NY, 10595, USA
- Department of Dermatology, New York Medical College, Valhalla, NY, 10595, USA
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11
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Lin S, Liu X, Jiang J, Ge W, Zhang Y, Li F, Tao Q, Liu S, Li M, Chen H. The involvement of keratinocytes in pruritus of chronic inflammatory dermatosis. Exp Dermatol 2024; 33:e15142. [PMID: 39032085 DOI: 10.1111/exd.15142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 07/02/2024] [Accepted: 07/09/2024] [Indexed: 07/22/2024]
Abstract
Frequent itching and incessant scratching are commonly observed in various chronic inflammatory skin conditions, including atopic dermatitis and psoriasis. The persistent and prolonged nature of pruritus can worsen one's quality of life. Keratinocytes (KCs), the predominant cells of the epidermis, have been confirmed to interact with sensory neurons and immune cells and be involved in chronic skin inflammatory diseases associated with pruritus. Initially, KCs and sensory neurons form a unique synapse-like connection within the epidermis, serving as the structural foundation for their interaction. Additionally, several receptors, including toll-like receptors and protease-activated receptor 2, expressed on KCs, become activated in an inflammatory milieu. On the one hand, activated KCs are sources of pro-inflammatory cytokines and neurotrophic factors, such as adenosine triphosphate, thymic stromal lymphopoietin, and nerve growth factor, which directly or indirectly participate in stimulating sensory neurons, thereby contributing to the itch sensations. On the other hand, KCs also function as primary transducers alongside intraepidermal nerve endings, directly initiating pruritic responses. This review summarizes the current literature and highlights the critical role of KCs in the development and persistence of chronic itch in inflammatory skin disorders.
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Affiliation(s)
- Shiying Lin
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Liu
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Jiang
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenqiang Ge
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yinlian Zhang
- Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, China
- Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Fei Li
- Department of Dermatology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China
- Department of Dermatology, The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, China
| | - Qingxiao Tao
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Suwen Liu
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Man Li
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongxiang Chen
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Dermatology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China
- Department of Dermatology, The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
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12
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Laky K, Frischmeyer-Guerrerio PA. Development and dysfunction of structural cells in eosinophilic esophagitis. J Allergy Clin Immunol 2024; 153:1485-1499. [PMID: 38849184 PMCID: PMC11626564 DOI: 10.1016/j.jaci.2024.04.006] [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: 12/18/2023] [Revised: 04/18/2024] [Accepted: 04/18/2024] [Indexed: 06/09/2024]
Abstract
Eosinophilic esophagitis (EoE) is a disorder characterized by dysfunction and chronic local inflammation of the esophagus. The incidence and prevalence of EoE are increasing worldwide. The mechanisms responsible are poorly understood, and effective treatment options are limited. From the lumen outward, the esophagus comprises stratified squamous epithelium, lamina propria, and muscle. The tissue-specific nature of EoE strongly suggests that structural cells in the esophagus are involved in the EoE diathesis. Epithelial basal cell hyperplasia and dilated intercellular spaces are cardinal features of EoE. Some patients with EoE develop lamina propria fibrosis, strictures, or esophageal muscle dysmotility. Clinical symptoms of EoE are only weakly correlated with peak eosinophil count, implying that other cell types contribute to EoE pathogenesis. Epithelial, endothelial, muscle, and fibroblast cells can each initiate inflammation and repair, regulate tissue resident immune cells, recruit peripheral leukocytes, and tailor adaptive immune cell responses. A better understanding of how structural cells maintain tissue homeostasis, respond to cell-intrinsic and cell-extrinsic stressors, and exacerbate and/or resolve inflammatory responses in the esophagus is needed. This knowledge will facilitate the development of more efficacious treatment strategies for EoE that can restore homeostasis of both hematopoietic and structural elements in the esophagus.
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Affiliation(s)
- Karen Laky
- Food Allergy Research Section, Laboratory of Allergic Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
| | - Pamela A Frischmeyer-Guerrerio
- Food Allergy Research Section, Laboratory of Allergic Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
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13
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Zhang S, Fang X, Xu B, Zhou Y, Li F, Gao Y, Luo Y, Yao X, Liu X. Comprehensive analysis of phenotypes and transcriptome characteristics reveal the best atopic dermatitis mouse model induced by MC903. J Dermatol Sci 2024; 114:104-114. [PMID: 38806322 DOI: 10.1016/j.jdermsci.2024.05.003] [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: 01/05/2024] [Revised: 04/01/2024] [Accepted: 05/13/2024] [Indexed: 05/30/2024]
Abstract
BACKGROUND Although several mouse models of exogenous-agent-induced atopic dermatitis (AD) are currently available, the lack of certainty regarding their similarity with human AD has limited their scientific value. Thus, comprehensive evaluation of the characteristics of mouse models and their similarity with human AD is essential. OBJECTIVE To compare six different exogenous-agent-induced AD mouse models and find out the optimum models for study. METHODS Female BALB/c mice underwent induction of AD-like dermatitis by MC903 alone or in combination with ovalbumin (OVA), dinitrofluorobenzene (DNFB) alone or in combination with OVA, OVA alone, or Staphylococcus aureus. Gross phenotype, total immunoglobulin E (IgE) level, histopathological manifestations, and skin lesion transcriptome were analyzed, and metagenomic sequencing of the gut microbiome was performed. RESULTS The DNFB plus OVA model showed the highest disease severity, while the OVA model showed the lowest severity. The MC903 and MC903 plus OVA models showed high expression of T-helper (Th)2- and Th17-related genes; the DNFB and DNFB plus OVA models showed upregulation of Th1-, Th2-, and Th17-related genes; while the S. aureus inoculation model showed more enhanced Th1 and Th17 immune responses. In contrast to the other models, the OVA-induced model showed the lowest expression levels of inflammation-related genes, while the MC903 model shared the largest overlap with human AD profiles. The intestinal microbiota of all groups showed significant differences after modeling. CONCLUSION Each AD mouse model exhibited different characteristics. The MC903 model was the best to recapitulate most features of human AD among these exogenous-agent-induced AD models.
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Affiliation(s)
- Shan Zhang
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Xiaokai Fang
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Beilei Xu
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Yuan Zhou
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Fang Li
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Yuwen Gao
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Yang Luo
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Xu Yao
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
| | - Xiaochun Liu
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
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14
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Li L, Li ZE, Mo YL, Li WY, Li HJ, Yan GH, Qin XZ, Piao LH. Molecular and cellular pruritus mechanisms in the host skin. Exp Mol Pathol 2024; 136:104889. [PMID: 38316203 DOI: 10.1016/j.yexmp.2024.104889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 12/28/2023] [Accepted: 01/31/2024] [Indexed: 02/07/2024]
Abstract
Pruritus, also known as itching, is a complex sensation that involves the activation of specific physiological and cellular receptors. The skin is innervated with sensory nerves as well as some receptors for various sensations, and its immune system has prominent neurological connections. Sensory neurons have a considerable impact on the sensation of itching. However, immune cells also play a role in this process, as they release pruritogens. Disruption of the dermal barrier activates an immune response, initiating a series of chemical, physical, and cellular reactions. These reactions involve various cell types, including keratinocytes, as well as immune cells involved in innate and adaptive immunity. Collective activation of these immune responses confers protection against potential pathogens. Thus, understanding the molecular and cellular mechanisms that contribute to pruritus in host skin is crucial for the advancement of effective treatment approaches. This review provides a comprehensive analysis of the present knowledge concerning the molecular and cellular mechanisms underlying itching signaling in the skin. Additionally, this review explored the integration of these mechanisms with the broader context of itch mediators and the expression of their receptors in the skin.
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Affiliation(s)
- Li Li
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, China; Department of Anatomy, Yanbian University Medical College, Yanji 133002, China
| | - Zhi-En Li
- Clinical Medicine, Yanbian University Medical College, Yanji 133002, China
| | - Yun-Li Mo
- Clinical Medicine, Yanbian University Medical College, Yanji 133002, China
| | - Wan-Yao Li
- Clinical Medicine, Yanbian University Medical College, Yanji 133002, China
| | - Hui-Jing Li
- Clinical Medicine, Yanbian University Medical College, Yanji 133002, China
| | - Guang-Hai Yan
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, China; Department of Anatomy, Yanbian University Medical College, Yanji 133002, China
| | - Xiang-Zheng Qin
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, China; Department of Anatomy, Yanbian University Medical College, Yanji 133002, China.
| | - Li-Hua Piao
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, China; Department of Anatomy, Yanbian University Medical College, Yanji 133002, China.
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15
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Yamamura Y, Nakashima C, Otsuka A. Interplay of cytokines in the pathophysiology of atopic dermatitis: insights from Murin models and human. Front Med (Lausanne) 2024; 11:1342176. [PMID: 38590314 PMCID: PMC10999685 DOI: 10.3389/fmed.2024.1342176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 02/26/2024] [Indexed: 04/10/2024] Open
Abstract
The pathogenesis of atopic dermatitis (AD) is understood to be crucially influenced by three main factors: dysregulation of the immune response, barrier dysfunction, and pruritus. In the lesional skin of AD, various innate immune cells, including Th2 cells, type 2 innate lymphoid cells (ILC2s), and basophils, produce Th2 cytokines [interleukin (IL)-4, IL-5, IL-13, IL-31]. Alarmins such as TSLP, IL-25, and IL-33 are also produced by epidermal keratinocytes, amplifying type 2 inflammation. In the chronic phase, not only Th2 cells but also Th22 and Th17 cells increase in number, leading to suppression of filaggrin expression by IL-4, IL-13, and IL-22, which further deteriorates the epidermal barrier function. Dupilumab, which targets IL-4 and IL-13, has shown efficacy in treating moderate to severe AD. Nemolizumab, targeting IL-31RA, effectively reduces pruritus in AD patients. In addition, clinical trials with fezakinumab, targeting IL-22, have demonstrated promising results, particularly in severe AD cases. Conversely, in murine models of AD, several cytokines, initially regarded as promising therapeutic targets, have not demonstrated sufficient efficacy in clinical trials. IL-33 has been identified as a potent activator of immune cells, exacerbating AD in murine models and correlating with disease severity in human patients. However, treatments targeting IL-33 have not shown sufficient efficacy in clinical trials. Similarly, thymic stromal lymphopoietin (TSLP), integral to type 2 immune responses, induces dermatitis in animal models and is elevated in human AD, yet clinical treatments like tezepelumab exhibit limited efficacy. Therapies targeting IL-1α, IL-5, and IL-17 also failed to achieve sufficient efficacy in clinical trials. It has become clear that for treating AD, IL-4, IL-13, and IL-31 are relevant therapeutic targets during the acute phase, while IL-22 emerges as a target in more severe cases. This delineation underscores the necessity of considering distinct pathophysiological aspects and therapeutic targets in AD between mouse models and humans. Consequently, this review delineates the distinct roles of cytokines in the pathogenesis of AD, juxtaposing their significance in human AD from clinical trials against insights gleaned from AD mouse models. This approach will improve our understanding of interspecies variation and facilitate a deeper insight into the pathogenesis of AD in humans.
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Affiliation(s)
| | - Chisa Nakashima
- Department of Dermatology, Faculty of Medicine, Kindai University Hospital, Osaka, Japan
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16
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Miyagawa F, Ozato K, Tagaya Y, Asada H. Type I IFN Derived from Ly6C hi Monocytes Suppresses Type 2 Inflammation in a Murine Model of Atopic Dermatitis. J Invest Dermatol 2024; 144:520-530.e2. [PMID: 37739337 DOI: 10.1016/j.jid.2023.08.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 08/26/2023] [Accepted: 08/31/2023] [Indexed: 09/24/2023]
Abstract
The roles of innate immune cells, including eosinophils, basophils, and group 2 innate lymphoid cells, in atopic dermatitis (AD) have been well-documented, whereas that of monocytes, another component of the innate immunity, remains rather poorly understood, thus necessitating the topic of this study. In addition, cytokines and cellular pathways needed for the resolution of type 2 inflammation in AD need further investigation. Using a murine AD model, we report here that (i) Ly6Chi monocytes were rapidly recruited to the AD lesion in a CCR2-dependent manner, blockade of which exacerbated AD; (ii) type I IFN production is profoundly involved in this suppression because the blockade of it by genetic depletion or antibody neutralization exacerbated AD; and (iii) Ly6Chi monocytes operate through the production of type I IFN because Ly6Chi monocytes from Irf7-null mice, which lack type I IFN production, failed to rescue Ccr2-/- mice from severe AD upon adoptive transfer. In addition, in vitro studies demonstrated type I IFN suppressed basophil expansion from bone marrow progenitor cells and survival of mature basophils. Collectively, our work suggests that Ly6Chi monocytes are the first and dominant inflammatory cells reaching AD lesions that negatively regulate type 2 inflammation through the production of type I IFN.
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Affiliation(s)
- Fumi Miyagawa
- Department of Dermatology, Nara Medical University School of Medicine, Nara, Japan.
| | - Keiko Ozato
- Laboratory of Molecular Growth Regulation, Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
| | - Yutaka Tagaya
- Cell Biology Lab, Division of Virology, Pathogenesis and Cancer, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Hideo Asada
- Department of Dermatology, Nara Medical University School of Medicine, Nara, Japan
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17
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Zhao Y, Zhu L, Yang L, Chen M, Sun P, Ma Y, Zhang D, Zhao Y, Jia H. In vitro and in vivo anti-eczema effect of Artemisia annua aqueous extract and its component profiling. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:117065. [PMID: 37604330 DOI: 10.1016/j.jep.2023.117065] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 08/07/2023] [Accepted: 08/17/2023] [Indexed: 08/23/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Artemisia annua L. belongs to the Asteraceae family and has a long history of clinical application in China. It has been widely used for centuries to treat fever, malaria, jaundice and some skin diseases (such as scabies and sores). Modern pharmacological studies have shown that it has anti-inflammatory, immunomodulatory, antimalarial and antibacterial effects. AIM OF STUDY This study aimed to investigate the anti-eczema effect of A. annua aqueous extract (AAE), profile its potential bioactive components and try to explore its possible underlying mechanisms. MATERIALS AND METHODS The MTT assay was employed to assess the cytotoxicity of AAE. The anti-eczema effect of AAE was evaluated using both an in vitro 3D epidermal inflammation model and an in vivo guinea pig itching model. The bioactive components of AAE were characterized by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry coupled with the UNIFI platform. RESULTS In this study, we found that AAE is safe for primary human skin keratinocytes at concentrations ranging from 31.3 μg/mL to 250 μg/mL. Further investigations indicate that AAE can increase the itching threshold, inhibit the expression of the inflammatory cytokine TSLP, and promote the expression of FLG mRNA. Additionally, the utilization of UPLC-QTOF/MS and UNIFI platform enabled us to identify 61 potential bioactive components of AAE, with sesquiterpenes and phenolic acids being the most abundant components. CONCLUSIONS In this study, the anti-inflammatory and anti-itch effects of the A. annua extract were revealed, along with sesquiterpenes and phenolic acids were identified as potential bioactive components according to literature. The AAE extract holds potential for utilization in the treatment of eczema.
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Affiliation(s)
- Yifan Zhao
- Artemisinin Research Center & Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Le Zhu
- Shanghai Jahwa United Co., Ltd., Shanghai, 200082, China
| | - Lan Yang
- Artemisinin Research Center & Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Mo Chen
- Shanghai Jahwa United Co., Ltd., Shanghai, 200082, China
| | - Peng Sun
- Artemisinin Research Center & Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Yue Ma
- Artemisinin Research Center & Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Dong Zhang
- Artemisinin Research Center & Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Ya Zhao
- Shanghai Jahwa United Co., Ltd., Shanghai, 200082, China.
| | - Haidong Jia
- Shanghai Jahwa United Co., Ltd., Shanghai, 200082, China
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18
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Gupta RK, Miller J, Croft M. TNF-like weak inducer of apoptosis inhibition is comparable to IL-13 blockade in ameliorating atopic dermatitis inflammation. Allergy 2024; 79:116-127. [PMID: 37650473 PMCID: PMC10840791 DOI: 10.1111/all.15879] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 06/29/2023] [Accepted: 08/03/2023] [Indexed: 09/01/2023]
Abstract
BACKGROUND Targeting IL-13 is highly efficacious in patients with Th2-biased atopic dermatitis (AD), but inhibition of other inflammatory molecules might also limit disease. We investigated the importance of the TNF family cytokine TNF-like weak inducer of apoptosis (TWEAK; TNFSF12) to keratinocyte dysregulation and the pathogenesis of AD in mice and also tested if blocking TWEAK has a similar therapeutic effect as targeting IL-13. METHODS Conditional knockout mice lacking Fn14 (TNFRSF12A), the receptor for TWEAK, only in keratinocytes, were repetitively sensitized with house dust mite allergen and analyzed for AD-like skin inflammation. To determine the translational potential, wild-type mice with AD were therapeutically treated with anti-TWEAK and/or anti-IL-13 antibodies, and skin inflammation was assessed. RESULTS Mice deficient in Fn14 in keratinocytes were resistant to developing maximal clinical features of AD, exhibiting reduced epidermal hyperplasia and dermal thickening, less skin infiltration of immune cells, and downregulated inflammatory gene expression. Moreover, therapeutic neutralization of TWEAK in wild-type mice with AD reduced all of the pathological features to a comparable extent as blocking IL-13. CONCLUSIONS The activity of TWEAK in keratinocytes contributes to AD development, and neutralizing TWEAK represents a future potential therapeutic option in human AD similar to targeting IL-13.
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Affiliation(s)
- Rinkesh K. Gupta
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
| | - Jacqueline Miller
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
| | - Michael Croft
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
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Jeong GH, Lee JH. Dysregulated Hippo Signaling Pathway and YAP Activation in Atopic Dermatitis: Insights from Clinical and Animal Studies. Int J Mol Sci 2023; 24:17322. [PMID: 38139151 PMCID: PMC10744022 DOI: 10.3390/ijms242417322] [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: 10/07/2023] [Revised: 12/06/2023] [Accepted: 12/08/2023] [Indexed: 12/24/2023] Open
Abstract
The yes-associated protein (YAP) of the Hippo pathway regulates a variety of target genes involved in cell proliferation, survival, and inflammation. YAP and transcription activator with a PDZ-binding motif (TAZ) proteins act as mediators of the inflammatory response. Still, their role in atopic dermatitis (AD)-particularly, the association with the nuclear factor kappa-B and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways-is not fully understood. In this study, we found that YAP, is upregulated in AD patients and NC/Nga mouse model of AD. In addition, inhibition of YAP significantly reduced epidermal cell proliferation by 58% and mast cell numbers by 51% and attenuated the upregulation of both Th1- and Th2-associated cytokines. Among the JAK-STAT family proteins, the expressions of JAK1 and JAK2 and those of STAT1, STAT2, and STAT3 were also downregulated. These findings may explain the role of YAP in AD and suggest YAP inhibitors as promising therapeutic agents for AD.
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Affiliation(s)
- Ga Hee Jeong
- Department of Biomedicine & Health Sciences, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea;
| | - Ji Hyun Lee
- Department of Biomedicine & Health Sciences, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea;
- Department of Dermatology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea
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García-Reyes MM, Zumaya-Pérez LC, Pastelin-Palacios R, Moreno-Eutimio MA. Serum thymic stromal lymphopoietin (TSLP) levels in atopic dermatitis patients: a systematic review and meta-analysis. Clin Exp Med 2023; 23:4129-4139. [PMID: 37515689 PMCID: PMC10725349 DOI: 10.1007/s10238-023-01147-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 07/18/2023] [Indexed: 07/31/2023]
Abstract
Thymic stromal lymphopoietin (TSLP) is critical in developing allergic responses, including atopic dermatitis (AD). We systematically reviewed the literature to complete a meta-analysis to quantitatively summarize the levels of serum TSLP in AD. The study was prospectively registered in the PROSPERO database (ID = CRD42021242628). The PUBMED, SCOPUS, and Cochrane Library databases were reviewed, and original articles investigating serum TSLP in AD patients were included. Differences in TSLP levels of AD patients and controls were summarized by standardized mean differences (SMD) using a random effects model. Study quality was assessed by applying the Newcastle‒Ottawa Scale. Fourteen studies, which included 1,032 AD patients and 416 controls, were included. Meta-analysis showed that TSLP levels were significantly higher in the AD group than in the control group (SMD = 2.21, 95% CI 1.37-3.06, p < 0.001). Stratification by geographical region, age, disease severity, TSLP determination method, sample size, and study quality revealed significantly elevated TSLP levels in European AD patients (SMD = 3.48, 95% CI 1.75-5.21, p < 0.0001), adult AD patients (SMD = 4.10, 95% CI 2.00-6.21, p < 0.0001), child AD patients (SMD = 0.83, 95% CI 0.08-1.59, p = 0.031), and all severity groups with AD compared with the control group (mild: SMD = 1.15, 95% CI 0.14-2.16, p = 0.025; moderate: SMD = 2.48, 95% CI 0.33-4.62, p = 0.024; and severe: SMD = 8.28, 95% CI 4.82-11.74, p = 2.72e-6). Noticeably, adults showed higher serum TSLP levels than children with AD, and serum TSL levels increased according to AD severity. In conclusion, our meta-analysis demonstrates that circulating TSLP levels are elevated in patients with AD. Future studies are warranted to further elucidate the sources of heterogeneity.
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Affiliation(s)
- Marlenne Marisol García-Reyes
- Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior S/N, Coyoacán, Cd. Universitaria, CP 04510, Mexico City, Mexico
- Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional (IPN), Manuel Carpio, Plutarco Elías Calles, Miguel Hidalgo, CP 11350, Mexico City, Mexico
| | - Luis Carlos Zumaya-Pérez
- Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior S/N, Coyoacán, Cd. Universitaria, CP 04510, Mexico City, Mexico
| | - Rodolfo Pastelin-Palacios
- Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior S/N, Coyoacán, Cd. Universitaria, CP 04510, Mexico City, Mexico
| | - Mario Adán Moreno-Eutimio
- Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior S/N, Coyoacán, Cd. Universitaria, CP 04510, Mexico City, Mexico.
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21
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Wang ZY, Zheng YX, Xu F, Cui YZ, Chen XY, Chen SQ, Yan BX, Zhou Y, Zheng M, Man XY. Epidermal keratinocyte-specific STAT3 deficiency aggravated atopic dermatitis-like skin inflammation in mice through TSLP upregulation. Front Immunol 2023; 14:1273182. [PMID: 38053996 PMCID: PMC10694200 DOI: 10.3389/fimmu.2023.1273182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 11/07/2023] [Indexed: 12/07/2023] Open
Abstract
Atopic dermatitis (AD) is one of the most common inflammatory skin diseases with complex pathogenesis involving epidermal barrier dysfunction, skin microbiome abnormalities and type-2-skewed immune dysregulation. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays critical roles in various biological processes. However, the role of STAT3 in epidermal keratinocytes in AD remains unclear. In this study, we generated an epidermal keratinocyte-specific Stat3-deficient mouse strain (termed Stat3 cKO mice). After topical 2,4-dinitrochlorobenzene (DNCB) treatment, Stat3 cKO mice developed worsened AD-like skin inflammation with increased Ki67+ cells, decreased filaggrin and loricrin expression, and downregulated S100A9 and LL37. The dominant microbial population in Stat3 cKO mice changed from Ralstonia to Staphylococcus. DNCB-treated Stat3 cKO mice displayed more infiltrating type-2 inflammatory cells, including mast cells, eosinophils, and CD4+T cells, accompanied by increased skin IL-4 and serum IgE levels. Moreover, thymic stromal lymphopoietin (TSLP), mainly produced by keratinocytes, was highly expressed in the ear skin of Stat3 cKO mice and chemoattracted more TSLPR+ cells. TSLP blockade significantly alleviated DNCB-induced AD-like skin inflammation in Stat3 cKO mice. Thus, epidermal keratinocyte-specific STAT3 deficiency can aggravate AD-like skin inflammation in mice, possibly through TSLP dysregulation.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Xiao-Yong Man
- Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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22
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Zhang Y. From gene identifications to therapeutic targets for asthma: Focus on great potentials of TSLP, ORMDL3, and GSDMB. CHINESE MEDICAL JOURNAL PULMONARY AND CRITICAL CARE MEDICINE 2023; 1:139-147. [PMID: 39171126 PMCID: PMC11332877 DOI: 10.1016/j.pccm.2023.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Indexed: 08/23/2024]
Abstract
Asthma is a chronic respiratory disease, and clinically, asthma exacerbations remain difficult to treat. The disease is caused by combinations of and interactions between genetic and environmental factors. Genomic and genetic approaches identified many novel genes to treat asthma and brought new insights into the disease. The products of the genes have functional roles in regulating physiological or pathophysiological processes in airway structural cells and immune system cells. Genetic factors also interact with environmental factors such as air pollutants, and bacterial and viral infections to trigger the disease. Thymic stromal lymphopoietin (TSLP), orosomucoid-like 3 (ORMDL3), and gasdermin B (GSDMB) are three genes identified by genetic studies to have a great potential as therapeutic targets of asthma. TSLP is an important driver of type 2 inflammation. ORMDL3 mediates cell stress, sphingolipid synthesis, and viral and bacterial infections. GSDMB regulates cell pyroptosis through its N and C terminals and can bind sulfatides to influence inflammatory response. Investigating inhibitors or modulators for these pathways would bring a new landscape for therapeutics of asthma in future.
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Affiliation(s)
- Youming Zhang
- National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK
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23
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Smolinska S, Antolín-Amérigo D, Popescu FD, Jutel M. Thymic Stromal Lymphopoietin (TSLP), Its Isoforms and the Interplay with the Epithelium in Allergy and Asthma. Int J Mol Sci 2023; 24:12725. [PMID: 37628907 PMCID: PMC10454039 DOI: 10.3390/ijms241612725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/25/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine that has emerged as a critical player in the development and progression of allergy and asthma. It is primarily produced by epithelial cells and functions as a potent immune system activator. TSLP acts through interaction with its receptor complex, composed of the TSLP receptor (TSLPR) and interleukin-7 receptor alpha chain (IL-7Rα), activating downstream complex signalling pathways. The TSLP major isoform, known as long-form TSLP (lfTSLP), is upregulated in the airway epithelium of patients with allergic diseases. More research is warranted to explore the precise mechanisms by which short-form TSLP (sfTSLP) regulates immune responses. Understanding the dynamic interplay between TSLP and the dysfunctional epithelium provides insights into the mechanisms underlying allergy and asthma pathogenesis. Targeting TSLP represents an important therapeutic strategy, as it may upstream disrupt the inflammatory cascade and alleviate symptoms associated with allergic inflammation.
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Affiliation(s)
- Sylwia Smolinska
- Department of Clinical Immunology, Wroclaw Medical University, 50-368 Wroclaw, Poland;
| | - Darío Antolín-Amérigo
- Servicio de Alergia, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain;
| | - Florin-Dan Popescu
- Department of Allergology “Nicolae Malaxa” Clinical Hospital, “Carol Davila” University of Medicine and Pharmacy, 022441 Bucharest, Romania;
| | - Marek Jutel
- Department of Clinical Immunology, Wroclaw Medical University, 50-368 Wroclaw, Poland;
- “ALL-MED” Research Medical Institute, 53-201 Wroclaw, Poland
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24
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Kopp EB, Agaronyan K, Licona-Limón I, Nish SA, Medzhitov R. Modes of type 2 immune response initiation. Immunity 2023; 56:687-694. [PMID: 37044059 DOI: 10.1016/j.immuni.2023.03.015] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/18/2023] [Accepted: 03/20/2023] [Indexed: 04/14/2023]
Abstract
Type 2 immunity defends against macro-parasites and can cause allergic diseases. Our understanding of the mechanisms governing the initiation of type 2 immunity is limited, whereas we know more about type 1 immune responses. Type 2 immunity can be triggered by a wide array of inducers that do not share common features and via diverse pathways and mechanisms. To address the complexity of the type 2 initiation pathways, we suggest a framework that conceptualizes different modes of induction of type 2 immunity. We discuss categories of type 2 inducers and their immunogenicity, types of tissue perturbations that are caused by these inducers, sensing strategies for the initiation of Th2 immune responses, and categorization of the signals that are produced in response to type 2 challenges. We describe tissue-specific examples of functional disruption that could lead to type 2 inflammation and propose that different sensing strategies that operate at the tissue level converge on the initiation of type 2 immune responses.
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Affiliation(s)
- Elizabeth B Kopp
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Karen Agaronyan
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, New Haven, CT 06510, USA
| | - Ileana Licona-Limón
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Simone A Nish
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Ruslan Medzhitov
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, New Haven, CT 06510, USA; Tananbaum Center for Theoretical and Analytical Human Biology, Yale University School of Medicine, New Haven, CT, USA.
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25
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Wang J, Zhou Y, Zhang H, Hu L, Liu J, Wang L, Wang T, Zhang H, Cong L, Wang Q. Pathogenesis of allergic diseases and implications for therapeutic interventions. Signal Transduct Target Ther 2023; 8:138. [PMID: 36964157 PMCID: PMC10039055 DOI: 10.1038/s41392-023-01344-4] [Citation(s) in RCA: 101] [Impact Index Per Article: 50.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 01/20/2023] [Accepted: 02/03/2023] [Indexed: 03/26/2023] Open
Abstract
Allergic diseases such as allergic rhinitis (AR), allergic asthma (AAS), atopic dermatitis (AD), food allergy (FA), and eczema are systemic diseases caused by an impaired immune system. Accompanied by high recurrence rates, the steadily rising incidence rates of these diseases are attracting increasing attention. The pathogenesis of allergic diseases is complex and involves many factors, including maternal-fetal environment, living environment, genetics, epigenetics, and the body's immune status. The pathogenesis of allergic diseases exhibits a marked heterogeneity, with phenotype and endotype defining visible features and associated molecular mechanisms, respectively. With the rapid development of immunology, molecular biology, and biotechnology, many new biological drugs have been designed for the treatment of allergic diseases, including anti-immunoglobulin E (IgE), anti-interleukin (IL)-5, and anti-thymic stromal lymphopoietin (TSLP)/IL-4, to control symptoms. For doctors and scientists, it is becoming more and more important to understand the influencing factors, pathogenesis, and treatment progress of allergic diseases. This review aimed to assess the epidemiology, pathogenesis, and therapeutic interventions of allergic diseases, including AR, AAS, AD, and FA. We hope to help doctors and scientists understand allergic diseases systematically.
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Affiliation(s)
- Ji Wang
- National Institute of TCM constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, P.R. China
| | - Yumei Zhou
- National Institute of TCM constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, P.R. China
| | - Honglei Zhang
- National Institute of TCM constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, P.R. China
| | - Linhan Hu
- National Institute of TCM constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, P.R. China
| | - Juntong Liu
- National Institute of TCM constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, P.R. China
| | - Lei Wang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 1000210, China
| | - Tianyi Wang
- National Institute of TCM constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, P.R. China
| | - Haiyun Zhang
- National Institute of TCM constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, P.R. China
| | - Linpeng Cong
- National Institute of TCM constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, P.R. China
| | - Qi Wang
- National Institute of TCM constitution and Preventive Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, P.R. China.
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Abstract
Atopic dermatitis (AD) is a chronic, relapsing, and extremely pruritic inflammatory skin disease with a particular impact on children. AD pathogenesis is not yet fully understood, and there is no curative treatment for this disease. Therefore, several genetically or chemically-induced AD mouse models have been developed. These preclinical mouse models are an indispensable research tool for studying AD pathogenesis and evaluating the efficacy of new candidate AD therapeutics. A commonly used mouse model of AD has been developed using the topical application of a low-calcemic analog of vitamin D3, MC903, to induce AD-like inflammatory phenotypes that closely resemble human AD. Moreover, this model shows a minimal effect on systemic calcium metabolism that is observed in the vitamin D3-induced AD model. Thus, an expanding number of studies use the MC903-induced AD model to interrogate AD pathobiology in vivo and to test new candidate small molecule and monoclonal antibody therapies. This protocol describes in detail functional measurements including the measurement of skin thickness, which is a surrogate marker for ear skin inflammation, as well as itch assessment, histological evaluation to assess the structural changes associated with AD skin inflammation, and preparation of single-cell suspensions from ear skin and draining lymph nodes for the assessment of inflammatory leukocyte subset infiltration in these tissues using flow cytometry. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Topical application of MC903 induces AD-like skin inflammation Support Protocol 1: Measurement of ear skin thickness Support Protocol 2: Itch assessment Support Protocol 3: Dissection of ear skin and ear draining lymph nodes Support Protocol 4: Histological evaluation and quantification Support Protocol 5: Preparation of single-cell suspension from ear skin and draining lymph nodes for the assessment of inflammatory immune cell infiltration using flow cytometry.
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Affiliation(s)
- Md Jahangir Alam
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Liang Xie
- Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Yu-Anne Yap
- Department of Physiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Remy Robert
- Department of Physiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
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27
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Ustaoglu E, Turkoglu Z, Ulgen OA, Caytemel C, Agirgol S. Anti-Inflammatory Effect of Cinnamaldehyde in a Mouse Model of 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis. Indian J Dermatol 2023; 68:170-177. [PMID: 37275806 PMCID: PMC10238997 DOI: 10.4103/ijd.ijd_576_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023] Open
Abstract
Background This study aims to investigate the anti-inflammatory effects of cinnamaldehyde in atopic dermatitis (AD) in the mouse model. Materials and Methods Twenty-four mice were divided into four groups: Group A (control), group B [AD with no treatment (AD + NoTre)], group C [AD with corticosteroids (AD + Cort)] and group D [AD with cinnamaldehyde (AD + Cin)]. 2,4-dinitrofluorobenzene was used to form the AD model. Topical corticosteroid was applied to group C, and oral cinnamaldehyde was administered to group D. Dorsal skin biopsies were evaluated immunohistochemically with interleukin (IL)-25, IL-33, thymic stromal lymphopoietin and caspase-3. Results Epithelial thicknesses were significantly higher in group B-D mice compared to group A (P = 0.002, 0.009, 0.004, respectively). Significantly, higher staining with IL-25 was observed in group B (AD + NoTre) and group D (AD + Cin) than in group A (control) (P = 0.003, 0.002, respectively). However, no significant difference was observed between group D (AD + Cin) and group B (AD + NoTre). All three groups (B-D) had significantly higher staining in terms of diffuseness of IL-33 compared to group A (control) (P = 0.002, 0.002, 0.002, respectively). Caspase-3 staining was significantly lower in group D (AD + Cin) than in group B (AD + NoTre) (P = 0.003, 0.002, respectively). Moreover, caspase-3 staining intensity was significantly lower in group D (AD + Cin) than in group C (AD + Cort) (P = 0.002). Conclusions Our study demonstrated that IL-33, IL-25 and caspase-3 have a role in the pathogenesis of AD. Furthermore, cinnamaldehyde reduced caspase-3 activity more than topical corticosteroids and anti-inflammatory effects might be investigated in AD therapy with future studies.
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Affiliation(s)
- Eda Ustaoglu
- From the Department of Dermatology, Bursa City Hospital, Bursa, Turkey
| | - Zafer Turkoglu
- Department of Dermatology, Basaksehir Cam and Sakura Hospital, Istanbul, Turkey
| | - Ovgu A. Ulgen
- Department of Pathology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Turkey
| | - Ceyda Caytemel
- Department of Dermatology, Basaksehir Cam and Sakura Hospital, Istanbul, Turkey
| | - Senay Agirgol
- Department of Dermatology, Basaksehir Cam and Sakura Hospital, Istanbul, Turkey
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28
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Abstract
INTRODUCTION The relationship between atopic dermatitis and atopic diseases such as food allergies, asthma, and allergic rhinitis in terms of co-occurrence, underlying mechanisms, and therapy is well documented. There is increasing evidence that atopic dermatitis is associated with non-atopic comorbidities such as cardiac, autoimmune, and neuropsychological comorbidities, as well as cutaneous and extracutaneous infections, establishing atopic dermatitis as a systemic disease. AREAS COVERED The authors reviewed evidence on atopic and non-atopic comorbidities of atopic dermatitis. A literature search was conducted in PubMed for peer-reviewed articles published until October 2022. EXPERT OPINION Atopic and non-atopic diseases coexist with atopic dermatitis more often than would be expected by chance. The effect of biologics and small molecules on atopic and non-atopic comorbidities may contribute to a better understanding of the relationship between atopic dermatitis and its comorbidities. Their relationship needs to be explored further to dismantle the underlying mechanism and move toward an atopic dermatitis endotype-based therapeutic approach.
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Affiliation(s)
- Caroline Gewiss
- Institute for Health Services Research in Dermatology and Nursing (IVDP), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
| | - Matthias Augustin
- Institute for Health Services Research in Dermatology and Nursing (IVDP), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
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29
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David E, Ungar B, Renert-Yuval Y, Facheris P, Del Duca E, Guttman-Yassky E. The evolving landscape of biologic therapies for atopic dermatitis: Present and future perspective. Clin Exp Allergy 2023; 53:156-172. [PMID: 36653940 DOI: 10.1111/cea.14263] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 11/05/2022] [Accepted: 11/23/2022] [Indexed: 01/20/2023]
Abstract
Atopic dermatitis (AD) is one of the most common, chronic inflammatory skin diseases with a significant physical, emotional and socioeconomic burden. In recent years the understanding of AD pathogenesis has expanded from the Th2-centred perspective, with the recognition of the involvement of other immune axes. In different AD endotypes, influenced by environment, genetics and race, transcriptomic profiles have identified differing contributions of multiple immune axes such as, Th17, Th22 and Th1. The enriched pathogenic model of AD has catalysed the development of numerous biologic therapies targeting a range of key molecules implicated in disease progression. Currently, dupilumab and tralokinumab, which both target the Th2 pathway, are the only approved biologic therapies for AD in the United States and Europe. New biologic therapies in development, however, target different Th2-pathway molecules along with cytokines in other immune axes, including Th17 and Th22, offering promise for varied treatments for this heterogeneous disease. As the biologic pipeline advances, the integration into clinical practice and approval of these experimental biologics may provide more effective, tailored therapeutic solutions and illuminate on the pathologic processes of AD across a broader, more diverse patient population.
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Affiliation(s)
- Eden David
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Benjamin Ungar
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Yael Renert-Yuval
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, USA
| | - Paola Facheris
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ester Del Duca
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Emma Guttman-Yassky
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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30
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Park HJ, Kataru RP, Shin J, Garc A Nores GD, Encarnacion EM, Klang MG, Riedel E, Coriddi M, Dayan JH, Mehrara BJ. Keratinocytes coordinate inflammatory responses and regulate development of secondary lymphedema. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.20.524936. [PMID: 36711669 PMCID: PMC9882288 DOI: 10.1101/2023.01.20.524936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Epidermal changes are histological hallmarks of secondary lymphedema, but it is unknown if keratinocytes contribute to its pathophysiology. Using clinical lymphedema specimens and mouse models, we show that keratinocytes play a primary role in lymphedema development by producing T-helper 2 (Th2) -inducing cytokines. Specifically, we find that keratinocyte proliferation and expression of protease-activated receptor 2 (PAR2) are early responses following lymphatic injury and regulate the expression of Th2-inducing cytokines, migration of Langerhans cells, and skin infiltration of Th2-differentiated T cells. Furthermore, inhibition of PAR2 activation with a small molecule inhibitor or the proliferation inhibitor teriflunomide (TF) prevents activation of keratinocytes stimulated with lymphedema fluid. Finally, topical TF is highly effective for decreasing swelling, fibrosis, and inflammation in a preclinical mouse model. Our findings suggest that lymphedema is a chronic inflammatory skin disease, and topically targeting keratinocyte activation may be a clinically effective therapy for this condition.
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31
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Singh CK, Mintie CA, Ndiaye MA, Chhabra G, Roy S, Sullivan R, Longley BJ, Schieke SM, Ahmad N. Protective effects of dietary grape against atopic dermatitis-like skin lesions in NC/NgaTndCrlj mice. Front Immunol 2023; 13:1051472. [PMID: 36741360 PMCID: PMC9893861 DOI: 10.3389/fimmu.2022.1051472] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/29/2022] [Indexed: 01/20/2023] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease with significant health/economic burdens. Existing therapies are not fully effective, necessitating development of new approaches for AD management. Here, we report that dietary grape powder (GP) mitigates AD-like symptoms in 2,4-dinitrofluorobenzene (DNFB)-induced AD in NC/NgaTndCrlj mice. Using prevention and intervention protocols, we tested the efficacy of 3% and 5% GP-fortified diet in a 13-weeks study. We found that GP feeding markedly inhibited development and progression of AD-like skin lesions, and caused reduction in i) epidermal thickness, mast cell infiltration, ulceration, excoriation and acanthosis in dorsal skin, ii) spleen weight, extramedullary hematopoiesis and lymph nodes sizes, and iii) ear weight and IgE levels. We also found significant modulations in 15 AD-associated serum cytokines/chemokines. Next, using quantitative global proteomics, we identified 714 proteins. Of these, 68 (normal control) and 21 (5% GP-prevention) were significantly modulated (≥2-fold) vs AD control (DNFB-treated) group, with many GP-modulated proteins reverting to normal levels. Ingenuity pathway analysis of GP-modulated proteins followed by validation using ProteinSimple identified changes in acute phase response signaling (FGA, FGB, FGG, HP, HPX, LRG1). Overall, GP supplementation inhibited DNFB-induced AD in NC/NgaTndCrlj mice in both prevention and intervention trials, and should be explored further.
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Affiliation(s)
- Chandra K. Singh
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
| | - Charlotte A. Mintie
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
| | - Mary A. Ndiaye
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
| | - Gagan Chhabra
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
| | - Sushmita Roy
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
| | - Ruth Sullivan
- Department of Comparative Biosciences, University of Wisconsin, Madison, WI, United States
| | - B. Jack Longley
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
| | - Stefan M. Schieke
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
| | - Nihal Ahmad
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
- William S. Middleton Veterans Affairs (VA) Medical Center, Madison, WI, United States
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Laky K, Kinard JL, Li JM, Moore IN, Lack J, Fischer ER, Kabat J, Latanich R, Zachos NC, Limkar AR, Weissler KA, Thompson RW, Wynn TA, Dietz HC, Guerrerio AL, Frischmeyer-Guerrerio PA. Epithelial-intrinsic defects in TGFβR signaling drive local allergic inflammation manifesting as eosinophilic esophagitis. Sci Immunol 2023; 8:eabp9940. [PMID: 36608150 PMCID: PMC10106118 DOI: 10.1126/sciimmunol.abp9940] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Allergic diseases are a global health challenge. Individuals harboring loss-of-function variants in transforming growth factor-β receptor (TGFβR) genes have an increased prevalence of allergic disorders, including eosinophilic esophagitis. Allergic diseases typically localize to mucosal barriers, implicating epithelial dysfunction as a cardinal feature of allergic disease. Here, we describe an essential role for TGFβ in the control of tissue-specific immune homeostasis that provides mechanistic insight into these clinical associations. Mice expressing a TGFβR1 loss-of-function variant identified in atopic patients spontaneously develop disease that clinically, immunologically, histologically, and transcriptionally recapitulates eosinophilic esophagitis. In vivo and in vitro, TGFβR1 variant-expressing epithelial cells are hyperproliferative, fail to differentiate properly, and overexpress innate proinflammatory mediators, which persist in the absence of lymphocytes or external allergens. Together, our results support the concept that TGFβ plays a fundamental, nonredundant, epithelial cell-intrinsic role in controlling tissue-specific allergic inflammation that is independent of its role in adaptive immunity.
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Affiliation(s)
- Karen Laky
- Food Allergy Research Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jessica L Kinard
- Food Allergy Research Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jenny Min Li
- Food Allergy Research Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ian N Moore
- Infectious Disease Pathogenesis Section, Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Justin Lack
- Collaborative Bioinformatics Resource, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.,Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Elizabeth R Fischer
- Electron Microscopy Unit, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
| | - Juraj Kabat
- Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Rachel Latanich
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Nicholas C Zachos
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Ajinkya R Limkar
- Inflammation Immunobiology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Katherine A Weissler
- Food Allergy Research Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Robert W Thompson
- Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Thomas A Wynn
- Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Harry C Dietz
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
| | - Anthony L Guerrerio
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Pamela A Frischmeyer-Guerrerio
- Food Allergy Research Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Abstract
Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine that acts on multiple cell lineages, including dendritic cells, T cells, B cells, neutrophils, mast cells, eosinophils and innate lymphoid cells, affecting their maturation, survival and recruitment. It is best known for its role in promoting type 2 immune responses such as in allergic diseases and, in 2021, a monoclonal antibody targeting TSLP was approved for the treatment of severe asthma. However, it is now clear that TSLP has many other important roles in a variety of settings. Indeed, several genetic variants for TSLP are linked to disease severity, and chromosomal alterations in TSLP are common in certain cancers, indicating important roles of TSLP in disease. In this Review, we discuss recent advances in TSLP biology, highlighting how it regulates the tissue environment not only in allergic disease but also in infectious diseases, inflammatory diseases and cancer. Encouragingly, therapies targeting the TSLP pathway are being actively pursued for several diseases.
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Affiliation(s)
- Risa Ebina-Shibuya
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Warren J Leonard
- Laboratory of Molecular Immunology, Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
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Luo J, Zhu Z, Zhai Y, Zeng J, Li L, Wang D, Deng F, Chang B, Zhou J, Sun L. The Role of TSLP in Atopic Dermatitis: From Pathogenetic Molecule to Therapeutical Target. Mediators Inflamm 2023; 2023:7697699. [PMID: 37096155 PMCID: PMC10122597 DOI: 10.1155/2023/7697699] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/25/2022] [Accepted: 10/10/2022] [Indexed: 04/26/2023] Open
Abstract
Atopic dermatitis (AD) is a kind of chronic skin disease with inflammatory infiltration, characterized by skin barrier dysfunction, immune response dysregulation, and skin dysbiosis. Thymic stromal lymphopoietin (TSLP) acts as a regulator of immune response, positively associated with AD deterioration. Mainly secreted by keratinocytes, TSLP interacts with multiple immune cells (including dendritic cells, T cells, and mast cells), following induction of Th2-oriented immune response during the pathogenesis of AD. This article primarily focuses on the TSLP biological function, the relationship between TSLP and different cell populations, and the AD treatments targeting TSLP.
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Affiliation(s)
- Jialiang Luo
- Department of Dermatology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhengyumeng Zhu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Yumeng Zhai
- Department of Dermatology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Junxiang Zeng
- Department of Bioinformation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Lei Li
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Di Wang
- Department of Dermatology, Dermatology Hospital of Southern Medical University, Southern Medical University, Guangzhou, Guangdong, China
| | - Fan Deng
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Bo Chang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Jia Zhou
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Ledong Sun
- Department of Dermatology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China
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35
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Peach CJ, Edgington-Mitchell LE, Bunnett NW, Schmidt BL. Protease-activated receptors in health and disease. Physiol Rev 2023; 103:717-785. [PMID: 35901239 PMCID: PMC9662810 DOI: 10.1152/physrev.00044.2021] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 07/08/2022] [Accepted: 07/10/2022] [Indexed: 11/22/2022] Open
Abstract
Proteases are signaling molecules that specifically control cellular functions by cleaving protease-activated receptors (PARs). The four known PARs are members of the large family of G protein-coupled receptors. These transmembrane receptors control most physiological and pathological processes and are the target of a large proportion of therapeutic drugs. Signaling proteases include enzymes from the circulation; from immune, inflammatory epithelial, and cancer cells; as well as from commensal and pathogenic bacteria. Advances in our understanding of the structure and function of PARs provide insights into how diverse proteases activate these receptors to regulate physiological and pathological processes in most tissues and organ systems. The realization that proteases and PARs are key mediators of disease, coupled with advances in understanding the atomic level structure of PARs and their mechanisms of signaling in subcellular microdomains, has spurred the development of antagonists, some of which have advanced to the clinic. Herein we review the discovery, structure, and function of this receptor system, highlight the contribution of PARs to homeostatic control, and discuss the potential of PAR antagonists for the treatment of major diseases.
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Affiliation(s)
- Chloe J Peach
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
- Department of Neuroscience and Physiology and Neuroscience Institute, Grossman School of Medicine, New York University, New York, New York
| | - Laura E Edgington-Mitchell
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
- Bluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, New York
| | - Nigel W Bunnett
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
- Department of Neuroscience and Physiology and Neuroscience Institute, Grossman School of Medicine, New York University, New York, New York
| | - Brian L Schmidt
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York
- Bluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, New York
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36
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β-Caryophyllene Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis through the Downregulation of Mitogen-Activated Protein Kinase/EGR1/TSLP Signaling Axis. Int J Mol Sci 2022; 23:ijms232314861. [PMID: 36499191 PMCID: PMC9740728 DOI: 10.3390/ijms232314861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/21/2022] [Accepted: 11/25/2022] [Indexed: 12/02/2022] Open
Abstract
Atopic dermatitis (AD) is one of the most common inflammatory skin diseases accompanied by severe itching. β-caryophyllene (BCP), which displays anti-inflammatory activity, is a natural agonist of cannabinoid receptor 2. However, the therapeutic effects of BCP on atopic dermatitis (AD) remain poorly understood. The current study aimed to evaluate the topical therapeutic efficacy of BCP in an AD-like mouse model. Thymic Stromal Lymphopoietin (TSLP) is a keratinocyte-derived cytokine that drives AD pathogenesis. This study also investigated the effect of BCP on the interleukin 4 (IL-4)-induced expression of TSLP in HaCaT keratinocytes. We found that the topical application of BCP alleviated AD-like skin inflammation and inhibited the infiltration of proinflammatory cells into skin lesions. Moreover, the topical application of BCP reduced EGR1 (Early Growth Response 1) and TSLP expression in AD-like skin lesions. We also found that BCP inhibited IL-4-induced TSLP expression by downregulating mitogen-activated protein kinase (MAPK)-mediated EGR1 expression in HaCaT keratinocytes. These findings demonstrate that BCP ameliorates DNCB-induced AD-like skin lesions through the downregulation of the MAPK/EGR1/TSLP signaling axis. BCP may be applicable for developing topical therapeutic agents for chronic skin inflammatory diseases, such as AD.
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37
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Trier AM, Kim BS. Insights into atopic dermatitis pathogenesis lead to newly approved systemic therapies. Br J Dermatol 2022; 188:698-708. [PMID: 36763703 DOI: 10.1093/bjd/ljac016] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 08/04/2022] [Accepted: 10/13/2022] [Indexed: 01/09/2023]
Abstract
Atopic dermatitis (AD) is a common inflammatory skin disease characterized by scaly, oozing skin and itch. In moderate-to-severe AD, treatment options have been historically very limited and off-label use has been a common method for disease management. For decades, ciclosporin A was the only systemic immunosuppressive drug approved in most European countries to address this major unmet medical need. However, increased understanding of the pathophysiology of AD has led to a revolution in the treatment of this potentially debilitating disease. Following the approval of the first biological therapy for AD in 2017, there has been a rapid expansion of compounds under development and four additional systemic therapies have been approved in Europe and the USA within the past 3 years alone. In this review, we underscore how key breakthroughs have transformed the therapeutic landscape of AD, leading to a major expansion of type 2 immunity-targeted biological therapies, exploration of neuroimmune modulatory agents, and interest in Janus kinase inhibition.
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Affiliation(s)
- Anna M Trier
- Washington University School of Medicine, St. Louis, MO, USA
| | - Brian S Kim
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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38
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Yao W, German B, Chraa D, Braud A, Hugel C, Meyer P, Davidson G, Laurette P, Mengus G, Flatter E, Marschall P, Segaud J, Guivarch M, Hener P, Birling MC, Lipsker D, Davidson I, Li M. Keratinocyte-derived cytokine TSLP promotes growth and metastasis of melanoma by regulating the tumor-associated immune microenvironment. JCI Insight 2022; 7:161438. [PMID: 36107619 PMCID: PMC9675576 DOI: 10.1172/jci.insight.161438] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 09/12/2022] [Indexed: 12/15/2022] Open
Abstract
Malignant melanoma is a major public health issue displaying frequent resistance to targeted therapy and immunotherapy. A major challenge lies in better understanding how melanoma cells evade immune elimination and how tumor growth and metastasis is facilitated by the tumor microenvironment. Here, we show that expression of the cytokine thymic stromal lymphopoietin (TSLP) by epidermal keratinocytes is induced by cutaneous melanoma in both mice and humans. Using genetically engineered models of melanoma and tumor cell grafting combined with TSLP-KO or overexpression, we defined a crosstalk between melanoma cells, keratinocytes, and immune cells in establishing a tumor-promoting microenvironment. Keratinocyte-derived TSLP is induced by signals derived from melanoma cells and subsequently acts via immune cells to promote melanoma progression and metastasis. Furthermore, we show that TSLP signals through TSLP receptor-expressing (TSLPR-expressing) DCs to play an unrecognized role in promoting GATA3+ Tregs expressing a gene signature including ST2, CCR8, ICOS, PD-1, CTLA-4, and OX40 and exhibiting a potent suppressive activity on CD8+ T cell proliferation and IFN-γ production. An analogous population of GATA3-expressing Tregs was also identified in human melanoma tumors. Our study provides insights into the role of TSLP in programming a protumoral immune microenvironment in cutaneous melanoma.
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Affiliation(s)
- Wenjin Yao
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France
| | - Beatriz German
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France
| | - Dounia Chraa
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France
| | - Antoine Braud
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France.,Dermatology Clinic, Strasbourg University Hospital, Strasbourg, France
| | - Cecile Hugel
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France
| | - Pierre Meyer
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France
| | - Guillaume Davidson
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France
| | - Patrick Laurette
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France
| | - Gabrielle Mengus
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France
| | - Eric Flatter
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France
| | - Pierre Marschall
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France
| | - Justine Segaud
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France
| | - Marine Guivarch
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France
| | - Pierre Hener
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France
| | | | - Dan Lipsker
- Dermatology Clinic, Strasbourg University Hospital, Strasbourg, France
| | - Irwin Davidson
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France
| | - Mei Li
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U 1258, University of Strasbourg, Illkirch, France
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39
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Comparison of cytokine mediators in type 2 inflammatory conditions on the skin and ocular surface. Curr Opin Allergy Clin Immunol 2022; 22:319-327. [DOI: 10.1097/aci.0000000000000842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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40
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Segaud J, Yao W, Marschall P, Daubeuf F, Lehalle C, German B, Meyer P, Hener P, Hugel C, Flatter E, Guivarch M, Clauss L, Martin SF, Oulad-Abdelghani M, Li M. Context-dependent function of TSLP and IL-1β in skin allergic sensitization and atopic march. Nat Commun 2022; 13:4703. [PMID: 36050303 PMCID: PMC9437001 DOI: 10.1038/s41467-022-32196-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 07/20/2022] [Indexed: 11/09/2022] Open
Abstract
Atopic diseases, including atopic dermatitis (AD) and asthma, affect a large proportion of the population, with increasing prevalence worldwide. AD often precedes the development of asthma, known as the atopic march. Allergen sensitization developed through the barrier-defective skin of AD has been recognized to be a critical step leading to asthma, in which thymic stromal lymphopoietin (TSLP) was previously shown to be critical. In this study, using a laser-assistant microporation system to disrupt targeted skin layers for generating micropores at a precise anatomic depth of mouse skin, we model allergen exposure superficially or deeply in the skin, leading to epicutaneous sensitization or dermacutaneous sensitization that is associated with a different cytokine microenvironment. Our work shows a differential requirement for TSLP in these two contexts, and identifies an important function for IL-1β, which is independent of TSLP, in promoting allergen sensitization and subsequent allergic asthma. Allergic sensitisation in the skin can lead to allergic dermatitis and further to airway asthma in a process of atopic march. Here the authors examine the difference between superficial or deep skin sensitisation, characterise the immune cells generated and show differential TSLP and IL-1β involvement.
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Affiliation(s)
- Justine Segaud
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104 - Inserm U 1258 - Université de Strasbourg, Illkirch, France
| | - Wenjin Yao
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104 - Inserm U 1258 - Université de Strasbourg, Illkirch, France
| | - Pierre Marschall
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104 - Inserm U 1258 - Université de Strasbourg, Illkirch, France
| | - François Daubeuf
- CNRS-Strasbourg University, UAR3286, Plate-Forme de Chimie Biologique Intégrative de Strasbourg/Strasbourg Drug Discovery and Development Institute, ESBS, Illkirch, France.,CNRS-Strasbourg University, UMR7200, Laboratoire d'Innovation Thérapeutique/ Strasbourg Drug Discovery and Development Institute, Faculté de Pharmacie, Illkirch, France
| | - Christine Lehalle
- CNRS-Strasbourg University, UAR3286, Plate-Forme de Chimie Biologique Intégrative de Strasbourg/Strasbourg Drug Discovery and Development Institute, ESBS, Illkirch, France.,CNRS-Strasbourg University, UMR7200, Laboratoire d'Innovation Thérapeutique/ Strasbourg Drug Discovery and Development Institute, Faculté de Pharmacie, Illkirch, France
| | - Beatriz German
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104 - Inserm U 1258 - Université de Strasbourg, Illkirch, France
| | - Pierre Meyer
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104 - Inserm U 1258 - Université de Strasbourg, Illkirch, France
| | - Pierre Hener
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104 - Inserm U 1258 - Université de Strasbourg, Illkirch, France
| | - Cécile Hugel
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104 - Inserm U 1258 - Université de Strasbourg, Illkirch, France
| | - Eric Flatter
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104 - Inserm U 1258 - Université de Strasbourg, Illkirch, France
| | - Marine Guivarch
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104 - Inserm U 1258 - Université de Strasbourg, Illkirch, France
| | - Laetitia Clauss
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104 - Inserm U 1258 - Université de Strasbourg, Illkirch, France
| | - Stefan F Martin
- Allergy Research Group, Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Mustapha Oulad-Abdelghani
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104 - Inserm U 1258 - Université de Strasbourg, Illkirch, France
| | - Mei Li
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104 - Inserm U 1258 - Université de Strasbourg, Illkirch, France.
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41
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Park NJ, Jo BG, Bong SK, Park SA, Lee S, Kim YK, Yang MH, Kim SN. Lobelia chinensis Extract and Its Active Compound, Diosmetin, Improve Atopic Dermatitis by Reinforcing Skin Barrier Function through SPINK5/LEKTI Regulation. Int J Mol Sci 2022; 23:ijms23158687. [PMID: 35955819 PMCID: PMC9369373 DOI: 10.3390/ijms23158687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/25/2022] [Accepted: 08/02/2022] [Indexed: 01/27/2023] Open
Abstract
The skin acts as a mechanical barrier that protects the body from the exterior environment, and skin barrier function is attributed to the stratum corneum (SC), which is composed of keratinocytes and skin lipids. Skin barrier homeostasis is maintained by a delicate balance between the differentiation and exfoliation of keratinocytes, and keratinocyte desquamation is regulated by members of the serine protease kalikrein (KLK) family and their endogenous inhibitor SPINK5/LEKTI (serine protease inhibitor Kazal type 5/lympho-epithelial Kazal-type-related inhibitor). Furthermore, SPINK5/LEKTI deficiency is involved in impaired skin barrier function caused by KLK over-activation. We sought to determine whether increased SPINK5/LEKTI expression ameliorates atopic dermatitis (AD) by strengthening skin barrier function using the ethanol extract of Lobelia chinensis (LCE) and its active compound, diosmetin, by treating human keratinocytes with UVB and using a DNCB-induced murine model of atopic dermatitis. LCE or diosmetin dose-dependently increased the transcriptional activation of SPINK5 promoter and prevented DNCB-induced skin barrier damage by modulating events downstream of SPINK5, that is, KLK, PAR2 (protease activated receptor 2), and TSLP (thymic stromal lymphopoietin). LCE or diosmetin normalized immune response in DNCB treated SKH-1 hairless mice as determined by reductions in serum immunoglobulin E and interleukin-4 levels and numbers of lesion-infiltrating mast cells. Our results suggest that LCE and diosmetin are good candidates for the treatment of skin barrier-disrupting diseases such as Netherton syndrome or AD, and that they do so by regulating SPINK5/LEKTI.
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Affiliation(s)
- No-June Park
- Natural Products Research Institute, Korea Institute of Science and Technology (KIST), Gangneung 25451, Korea
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul 02792, Korea
| | - Beom-Geun Jo
- College of Pharmacy, Pusan National University, Busan 46241, Korea
| | - Sim-Kyu Bong
- Natural Products Research Institute, Korea Institute of Science and Technology (KIST), Gangneung 25451, Korea
| | - Sang-a Park
- Natural Products Research Institute, Korea Institute of Science and Technology (KIST), Gangneung 25451, Korea
| | - Sullim Lee
- Department of Life Science, College of Bio-Nano Technology, Gachon University, Seongnam 13120, Korea
| | - Yong Kee Kim
- College of Pharmacy, Sookmyung Women’s University, Seoul 04310, Korea
| | - Min Hye Yang
- College of Pharmacy, Pusan National University, Busan 46241, Korea
- Correspondence: (M.H.Y.); (S.-N.K.); Tel.: +82-51-513-6754 (M.H.Y.); +82-33-650-3503 (S.-N.K.)
| | - Su-Nam Kim
- Natural Products Research Institute, Korea Institute of Science and Technology (KIST), Gangneung 25451, Korea
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul 02792, Korea
- Correspondence: (M.H.Y.); (S.-N.K.); Tel.: +82-51-513-6754 (M.H.Y.); +82-33-650-3503 (S.-N.K.)
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Sanjel B, Shim WS. The contribution of mouse models to understanding atopic dermatitis. Biochem Pharmacol 2022; 203:115177. [PMID: 35843300 DOI: 10.1016/j.bcp.2022.115177] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 07/08/2022] [Accepted: 07/11/2022] [Indexed: 12/28/2022]
Abstract
Atopic dermatitis (AD) is a dermatological disease accompanied by dry and cracked skin with severe pruritus. Although various therapeutic strategies have been introduced to alleviate AD, it remains challenging to cure the disorder. To achieve such a goal, understanding the pathophysiological mechanisms of AD is a prerequisite, requiring mouse models that properly reflect the AD phenotypes. Currently, numerous AD mouse models have been established, but each model has its own advantages and weaknesses. In this review, we categorized and summarized mouse models of AD and described their characteristics from a researcher's perspective.
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Affiliation(s)
- Babina Sanjel
- College of Pharmacy, Gachon University, Hambangmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea; Gachon Institute of Pharmaceutical Sciences, Hambangmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea
| | - Won-Sik Shim
- College of Pharmacy, Gachon University, Hambangmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea; Gachon Institute of Pharmaceutical Sciences, Hambangmoero 191, Yeonsu-gu, Incheon 21936, Republic of Korea.
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Tanzer J, Meng D, Ohsaki A, Caldwell JM, Mingler MK, Rothenberg ME, Oyoshi MK. Laundry detergent promotes allergic skin inflammation and esophageal eosinophilia in mice. PLoS One 2022; 17:e0268651. [PMID: 35759448 PMCID: PMC9236249 DOI: 10.1371/journal.pone.0268651] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 05/04/2022] [Indexed: 11/24/2022] Open
Abstract
The prevalence of allergic diseases is on the rise, yet the environmental factors that contribute to this increase are still being elucidated. Laundry detergent (LD) that contains cytotoxic ingredients including microbial enzymes continuously comes into contact with the skin starting in infancy. An impaired skin barrier has been suggested as a route of allergic sensitization. We hypothesized that exposure of skin to LD damages the skin barrier resulting in systemic sensitization to allergens that enter through the impaired skin barrier. Mouse skin samples exposed in vitro to microbial proteases or LD exhibited physical damage, which was more pronounced in neonatal skin as compared to adult skin. Exposure of the skin to microbial proteases in vitro resulted in an increase in the levels of interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP). BALB/c wild type mice epicutaneously exposed to LD and ovalbumin (OVA) showed an increase in levels of transepidermal water loss, serum OVA-specific immunoglobulin (Ig) G1 and IgE antibodies, and a local increase of Il33, Tslp, Il4 and Il13 compared with LD or OVA alone. Following intranasal challenge with OVA, mice epicutaneously exposed to LD showed an increase in allergen-induced esophageal eosinophilia compared with LD or OVA alone. Collectively, these results suggest that LD may be an important factor that impairs the skin barrier and leads to allergen sensitization in early life, and therefore may have a role in the increase in allergic disease.
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Affiliation(s)
- Jamie Tanzer
- Harvard College, Cambridge, MA, United States of America
| | - Di Meng
- Division of Pediatric Allergy, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Charlestown, MA, United States of America
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States of America
| | - Asa Ohsaki
- Division of Immunology, Boston Children’s Hospital, Boston, MA, United States of America
| | - Julie M. Caldwell
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America
| | - Melissa K. Mingler
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America
| | - Marc E. Rothenberg
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America
| | - Michiko K. Oyoshi
- Division of Pediatric Allergy, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Charlestown, MA, United States of America
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States of America
- Division of Immunology, Boston Children’s Hospital, Boston, MA, United States of America
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Cytokines and chemokines modulation of itch. Neuroscience 2022; 495:74-85. [PMID: 35660453 DOI: 10.1016/j.neuroscience.2022.05.035] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/07/2022] [Accepted: 05/26/2022] [Indexed: 12/31/2022]
Abstract
Itch (pruritus) is a common cutaneous symptom widely associated with many skin complaints, and chronic itch can be a severe clinical problem. The onset and perpetuation of itch are linked to cytokines, such as interleukin (IL)-31, IL-4, IL-13, IL-33, thymic stromal lymphopoietin, and tumor necrosis factor-alpha, and chemokines, such as chemokine (C-C motif) ligand 2 and C-X-C motif chemokine ligand 10. This review highlights research that has attempted to determine the attributes of various cytokines and chemokines concerning the development and modulation of itch. Through such research, clinical approaches targeting cytokines and/or chemokines may arise, which may further the development of itch therapeutics.
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Saikosaponin A and Saikosaponin C Reduce TNF-α-Induced TSLP Expression through Inhibition of MAPK-Mediated EGR1 Expression in HaCaT Keratinocytes. Int J Mol Sci 2022; 23:ijms23094857. [PMID: 35563251 PMCID: PMC9105331 DOI: 10.3390/ijms23094857] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/23/2022] [Accepted: 04/24/2022] [Indexed: 12/12/2022] Open
Abstract
Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases worldwide, characterized by intense pruritus and eczematous lesions. Aberrant expression of thymic stromal lymphopoietin (TSLP) in keratinocytes is associated with the pathogenesis of AD and is considered a therapeutic target for the treatment of this disease. Saikosaponin A (SSA) and saikosaponin C (SSC), identified from Radix Bupleuri, exert anti-inflammatory effects. However, the topical effects of SSA and SSC on chronic inflammatory skin diseases are unclear. In this study, we investigated the effects of SSA and SSC on TSLP suppression in an AD-like inflammatory environment. We observed that SSA and SSC suppressed tumor necrosis factor-α-induced TSLP expression by downregulating the expression of the transcription factor early growth response 1 (EGR1) via inhibition of the extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase 1/2, and p38 mitogen-activated protein kinase pathways. We also confirmed that topical application of SSA or SSC reduced AD-like skin lesions in BALB/c mice challenged with 2,4-dinitrochlorobenzene. Our findings suggest that suppression of EGR1-regulated TSLP expression in keratinocytes might be attributable to the anti-inflammatory effects of SSA and SSC in AD-like skin lesions.
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Alsabbagh M, Ismaeel A. The role of cytokines in atopic dermatitis: a breakthrough in immunopathogenesis and treatment. ACTA DERMATOVENEROLOGICA ALPINA PANNONICA ET ADRIATICA 2022. [DOI: 10.15570/actaapa.2022.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Chung EJ, Luo CH, Thio CLP, Chang YJ. Immunomodulatory Role of Staphylococcus aureus in Atopic Dermatitis. Pathogens 2022; 11:pathogens11040422. [PMID: 35456097 PMCID: PMC9025081 DOI: 10.3390/pathogens11040422] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/23/2022] [Accepted: 03/29/2022] [Indexed: 12/24/2022] Open
Abstract
Staphylococcus aureus is a gram-positive bacterium commonly found on humans, and it constitutes the skin microbiota. Presence of S. aureus in healthy individuals usually does not pose any threat, as the human body is equipped with many mechanisms to prevent pathogen invasion and infection. However, colonization of S. aureus has been correlated with many healthcare-associated infections, and has been found in people with atopic diseases. In atopic dermatitis, constant fluctuations due to inflammation of the epidermal and mucosal barriers can cause structural changes and allow foreign antigens and pathogens to bypass the first line of defense of the innate system. As they persist, S. aureus can secrete various virulence factors to enhance their survival by host invasion and evasion mechanisms. In response, epithelial cells can release damage-associated molecular patterns, or alarmins such as TSLP, IL-25, IL-33, and chemokines, to recruit innate and adaptive immune cells to cause inflammation. Until recently, IL-36 had been found to play an important role in modulating atopic dermatitis. Secretion of IL-36 from keratinocytes can activate a Th2 independent pathway to trigger symptoms of allergic reaction resulting in clinical manifestations. This mini review aims to summarize the immunomodulatory roles of S. aureus virulence factors and how they contribute to the pathogenesis of atopic diseases.
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Affiliation(s)
- Ethan Jachen Chung
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115024, Taiwan; (E.J.C.); (C.-H.L.); (C.L.-P.T.)
- Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
| | - Chia-Hui Luo
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115024, Taiwan; (E.J.C.); (C.-H.L.); (C.L.-P.T.)
- Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
| | - Christina Li-Ping Thio
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115024, Taiwan; (E.J.C.); (C.-H.L.); (C.L.-P.T.)
| | - Ya-Jen Chang
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115024, Taiwan; (E.J.C.); (C.-H.L.); (C.L.-P.T.)
- Institute of Translational Medicine and New Drug Development, China Medical University, Taichung 406040, Taiwan
- Correspondence:
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Steinhoff M, Ahmad F, Pandey A, Datsi A, AlHammadi A, Al-Khawaga S, Al-Malki A, Meng J, Alam M, Buddenkotte J. Neuro-immune communication regulating pruritus in atopic dermatitis. J Allergy Clin Immunol 2022; 149:1875-1898. [PMID: 35337846 DOI: 10.1016/j.jaci.2022.03.010] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 02/13/2022] [Accepted: 03/10/2022] [Indexed: 11/26/2022]
Abstract
Atopic dermatitis (AD) is a common, chronic-relapsing inflammatory skin disease with significant disease burden. Genetic and environmental trigger factors contribute to AD, activating two of our largest organs, the nervous and immune system. Dysregulation of neuro-immune circuits plays a key role in the pathophysiology of AD causing inflammation, pruritus, pain, and barrier dysfunction. Sensory nerves can be activated by environmental or endogenous trigger factors transmitting itch stimuli to the brain. Upon stimulation, sensory nerve endings also release neuromediators into the skin contributing again to inflammation, barrier dysfunction and itch. Additionally, dysfunctional peripheral and central neuronal structures contribute to neuroinflammation, sensitization, nerve elongation, neuropathic itch, thus chronification and therapy-resistance. Consequently, neuro-immune circuits in skin and central nervous system may be targets to treat pruritus in AD. Cytokines, chemokines, proteases, lipids, opioids, ions excite/sensitize sensory nerve endings not only induce itch but further aggravate/perpetuate inflammation, skin barrier disruption, and pruritus. Thus, targeted therapies for neuro-immune circuits as well as pathway inhibitors (e.g., kinase inhibitors) may be beneficial to control pruritus in AD either in systemic and/or topical form. Understanding neuro-immune circuits and neuronal signaling will optimize our approach to control all pathological mechanisms in AD, inflammation, barrier dysfunction and pruritus.
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Affiliation(s)
- 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; Qatar University, College of Medicine, Doha, Qatar; Department of Dermatology, Weill Cornell Medicine, New York, USA.
| | - Fareed Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Atul Pandey
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Angeliki Datsi
- Institute for Transplantational Diagnostics and Cell Therapeutics, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Ayda AlHammadi
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar
| | - Sara Al-Khawaga
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar
| | - Aysha Al-Malki
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar
| | - Jianghui Meng
- National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland
| | - Majid Alam
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - 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
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Roediger B, Schlapbach C. T cells in the skin: lymphoma and inflammatory skin disease. J Allergy Clin Immunol 2022; 149:1172-1184. [PMID: 35247433 DOI: 10.1016/j.jaci.2022.02.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 02/23/2022] [Accepted: 02/23/2022] [Indexed: 11/17/2022]
Abstract
T cells are established contributors to the pathogenesis of atopic dermatitis (AD) and psoriasis, yet whether they are the key drivers or simply unwitting participants remains incompletely understood. Conversely, malignant T cells are the undisputed culprits of cutaneous T cell lymphoma (CTCL), a group of diseases that share key clinical, histopathological and molecular features with inflammatory skin disease (ISD). Here, we compare the pathogenesis of ISD and CTCL and discuss the resulting insights. Recurrent, skin-limited disease implicates skin-resident T cells (TRM) in both ISD and CTCL. In CTCL, malignant T cells recruit benign T cells into inflammatory skin lesions, a disease-amplifying function also proposed for pathogenic T cells in ISD. Mechanistically, cytokines produced by malignant T cells in CTCL and by pathogenic T cells in ISD, respectively, are likely both necessary and sufficient to drive skin inflammation and pruritus, which in turn promotes skin barrier dysfunction and dysbiosis. Therapies for ISD target T cell effector functions but do not address the chronicity of disease while treatments for CTCL target malignant T cells but not primarily the symptoms of the disease. By integrating our understanding of ISD and CTCL, important insights into pathogenesis and therapy can be made which may improve the lives of sufferers of both disease groups.
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Affiliation(s)
- Ben Roediger
- Autoimmunity, Transplantation and Inflammation (ATI), Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland
| | - Christoph Schlapbach
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
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50
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Habibi S, Ramazanali F, Favaedi R, Afsharian P, Amirchaghmaghi E, Shahhoseini M. Thymic stromal lymphopoietin (TSLP) is a potent pro-inflammatory mediator which is epigenetically deregulated in endometriosis. J Reprod Immunol 2022; 151:103515. [DOI: 10.1016/j.jri.2022.103515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 03/01/2022] [Accepted: 03/14/2022] [Indexed: 10/18/2022]
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