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Yin K, Villareal L, Wu X, Arcos M, Lee J, Martin DR, In JG, Leslie K, Zhang DD, Xue X. The STEAP4 target NQO1 mediates colon tumorigenesis. J Cell Sci 2025; 138:jcs263402. [PMID: 40205952 DOI: 10.1242/jcs.263402] [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: 06/22/2024] [Accepted: 03/18/2025] [Indexed: 04/11/2025] Open
Abstract
Colorectal cancer (CRC) remains a major global health concern, necessitating advancements in therapeutic strategies. Understanding the mechanisms driving CRC is crucial for developing effective treatments. Previous studies, including our own, highlight the role of six-transmembrane epithelial antigen of prostate 4 (STEAP4) in promoting colon tumorigenesis through reactive oxygen species (ROS) generation, making it a promising target. Our research provides compelling evidence that STEAP4 knockout significantly reduces colon tumorigenesis in a genetically engineered mouse model. Suppressing STEAP4 via knockdown techniques effectively attenuated the nuclear factor erythroid 2-related factor 2 (NRF2)-NAD(P)H:quinone oxidoreductase 1 (NQO1) signaling pathway, inducing apoptosis and autophagy, leading to substantial reductions in xenograft tumor growth. In contrast, STEAP4 overexpression amplified ROS production and activated the NRF2-NQO1 pathway in a ferric iron (Fe3+)-dependent manner. Notably, bioactivatable drugs targeting NQO1 were highly effective at eradicating STEAP4-overexpressing colon cancer cells. These findings highlight the potential of targeted therapeutic interventions for CRC, particularly through STEAP4 modulation. In conclusion, our study advances understanding of the role of STEAP4 in colon tumorigenesis, offering promising avenues for novel CRC treatments.
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Affiliation(s)
- Kunlun Yin
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA
| | - Luke Villareal
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA
| | - Xiangxiang Wu
- Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
| | - Mariella Arcos
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA
| | - Jordan Lee
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA
| | - David R Martin
- Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA
| | - Julie G In
- Division of Gastroenterology, Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
| | - Kimberly Leslie
- Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
| | - Donna D Zhang
- Center for Inflammation Science and Systems Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA
| | - Xiang Xue
- Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA
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Cai Q, Jing C, Wang X, Xing X, Liu W. STEAP Proteins: Roles in disease biology and potential for therapeutic intervention. Int J Biol Macromol 2025; 309:142797. [PMID: 40185436 DOI: 10.1016/j.ijbiomac.2025.142797] [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: 12/08/2024] [Revised: 03/25/2025] [Accepted: 04/01/2025] [Indexed: 04/07/2025]
Abstract
Iron and copper are essential metal ions, and maintaining their metabolic balance is critical for organismal health. The Six-Transmembrane Epithelial Antigen of the Prostate (STEAP) protein family, comprising STEAP1, STEAP2, STEAP3, and STEAP4, plays a vital role in cellular metal homeostasis. These proteins are located on the cell membrane and are characterized by six transmembrane domains. With the exception of STEAP1, the STEAP proteins function as metal oxidoreductases due to their F420H2:NADP+ oxidoreductase (FNO)-like domain. However, STEAP1 contributes to metal metabolism through its heme group and interaction with other STEAP proteins. Beyond metal metabolism, STEAP proteins are involved in critical cellular processes, including the regulation of the cell cycle, proliferation, differentiation, and apoptosis. Notably, STEAP proteins are recognized as potential biomarkers and therapeutic targets in human cancers, particularly prostate cancer. This review outlines the structural features and functional roles of STEAP proteins in various diseases, including cancers, insulin resistance, non-alcoholic fatty liver disease (NAFLD), and benign prostatic hyperplasia, with a focus on their potential for therapeutic intervention.
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Affiliation(s)
- Qiaomei Cai
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin 300060, PR China
| | - Chao Jing
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin 300060, PR China
| | - Xudong Wang
- Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin 300060, PR China
| | - Xiangling Xing
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, PR China.
| | - Wancheng Liu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, PR China.
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Chen CH, Wu NL, Tsai TF. How Cells Die in Psoriasis? Int J Mol Sci 2025; 26:3747. [PMID: 40332377 PMCID: PMC12027842 DOI: 10.3390/ijms26083747] [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: 03/28/2025] [Revised: 04/13/2025] [Accepted: 04/14/2025] [Indexed: 05/08/2025] Open
Abstract
Psoriasis, a chronic immune-mediated inflammatory skin disorder characterized by keratinocyte hyperproliferation and inflammatory cell infiltration, involves multiple distinct programmed cell death pathways in its pathogenesis. Following the Nomenclature Committee on Cell Death recommendations, we analyzed the current literature examining diverse modes of cellular death in psoriatic lesions, with particular focus on keratinocyte cell death patterns and their molecular signatures. Analysis revealed several distinct cell death mechanisms: autophagy dysfunction through IL-17A pathways, decreased apoptotic activity in lesional skin, medication targeting anoikis in psoriasis, upregulated necroptosis mediated by RIPK1/MLKL signaling, gasdermin-mediated pyroptosis with enhanced IL-1β secretion, coordinated PANoptotic activation through specialized complexes, PARP1-mediated parthanatos promoting cutaneous inflammation, iron-dependent ferroptosis correlating with Th22/Th17 responses, copper-dependent cuproptosis with elevated MTF1/ATP7B/SLC31A1 expression, and NETosis amplifying immune responses through interaction with the Th17 axis. The intricate interplay between these cell death mechanisms has led to the development of targeted therapeutic strategies, including mTOR inhibitors for autophagy modulation, RIPK1 inhibitors for necroptosis, and various approaches targeting ferroptosis and NETosis, providing new directions for more effective psoriasis treatments.
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Affiliation(s)
- Chung-Han Chen
- Department of Education, National Taiwan University Hospital, Taipei City 100, Taiwan;
| | - Nan-Lin Wu
- Department of Dermatology, MacKay Memorial Hospital, Taipei City 104, Taiwan;
- Department of Medicine, MacKay Medical College, New Taipei City 252, Taiwan
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City 252, Taiwan
| | - Tsen-Fang Tsai
- Department of Dermatology, National Taiwan University Hospital, Taipei City 100, Taiwan
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Benezeder T, Bordag N, Woltsche J, Falkensteiner K, Graier T, Schadelbauer E, Cerroni L, Meyersburg D, Mateeva V, Reich A, Kołt-Kamińska M, Ratzinger G, Maul JT, Meier-Schiesser B, Navarini AA, Ceovic R, Prillinger K, Marovt M, Pavlovksy L, Szegedi A, Sanzharovskaja M, Zach H, Wolf P. IL-36-driven pustulosis: Transcriptomic signatures match between generalized pustular psoriasis (GPP) and acute generalized exanthematous pustulosis (AGEP). J Allergy Clin Immunol 2025:S0091-6749(25)00176-9. [PMID: 39978684 DOI: 10.1016/j.jaci.2025.01.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/22/2024] [Accepted: 01/14/2025] [Indexed: 02/22/2025]
Abstract
BACKGROUND Due to similarities, the distinction between generalized pustular psoriasis (GPP) and acute generalized exanthematous pustulosis (AGEP) has been a matter of debate for a long time. OBJECTIVES Our aim was to define the molecular features of GPP and AGEP. METHODS We analyzed skin biopsy samples and clinical data from 125 patients with AGEP, GPP, palmoplantar pustulosis (PPP), plaque psoriasis (PSO), and nonpustular cutaneous adverse drug reactions (ADRs), as well as from healthy skin controls using RNA-sequencing and blinded histopathologic analyses. RESULTS The transcriptome and histopathologic features of AGEP and GPP samples exhibited significant overlap (177 differentially expressed genes [DEGs] in GPP and AGEP compared to healthy skin, only 2 DEGs comparing AGEP and GPP). Yet, they displayed marked differences from those of PPP, PSO, and ADR samples, with a notable number of DEGs (131 DEGs comparing AGEP and PSO, 75 DEGs comparing AGEP and PPP, and 52 DEGs comparing AGEP and ADR). A transcriptome profile subgroup evaluation of >13,000 analyzed genes did not reveal any DEGs in drug-induced GPP and AGEP. Moreover, the immune response pattern and immune cell composition did not differ between drug-induced GPP and AGEP, whereas non-drug-induced GPP had higher expression of TH17-cell-related genes and a higher neutrophil count than AGEP. CONCLUSIONS We propose that AGEP is a drug-induced variant of GPP and therefore part of IL-36-related pustulosis. A key signature overarching this spectrum was identified, thereby opening the therapeutic approach of IL-36 inhibition to all subtypes of the disease.
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Affiliation(s)
- Theresa Benezeder
- Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - Natalie Bordag
- Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - Johannes Woltsche
- Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | | | - Thomas Graier
- Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - Eva Schadelbauer
- Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - Lorenzo Cerroni
- Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - Damian Meyersburg
- Department of Dermatology and Allergology, University Hospital Salzburg of the Paracelsus Medical University, Salzburg, Austria
| | - Valeria Mateeva
- Department of Dermatology and Venereology, Medical Faculty, Medical University, Sofia, Bulgaria
| | - Adam Reich
- Department of Dermatology, Faculty of Medicine, Medical College of Rzeszów University, Rzeszów, Poland
| | - Marta Kołt-Kamińska
- Department of Dermatology, Faculty of Medicine, Medical College of Rzeszów University, Rzeszów, Poland
| | - Gudrun Ratzinger
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Julia-Tatjana Maul
- Department of Dermatology, University of Zürich, Zürich, Switzerland; Faculty of Medicine, University of Zürich, Zürich, Switzerland
| | - Barbara Meier-Schiesser
- Department of Dermatology, University of Zürich, Zürich, Switzerland; Faculty of Medicine, University of Zürich, Zürich, Switzerland
| | | | - Romana Ceovic
- Department of Dermatology and Venereology, School of Medicine University of Zagreb, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Knut Prillinger
- Department of Dermatology, University Hospital St Pölten, St Pölten, Austria
| | - Maruska Marovt
- Department of Dermatology, University Medical Centre Maribor, Maribor, Slovenia
| | - Lev Pavlovksy
- Division of Dermatology, Rabin Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Andrea Szegedi
- Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | | | | | - Peter Wolf
- Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.
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Crosson T, Bhat S, Wang JC, Salaun C, Fontaine E, Roversi K, Herzog H, Rafei M, Blunck R, Talbot S. Cytokines reprogram airway sensory neurons in asthma. Cell Rep 2024; 43:115045. [PMID: 39661516 DOI: 10.1016/j.celrep.2024.115045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 10/01/2024] [Accepted: 11/18/2024] [Indexed: 12/13/2024] Open
Abstract
Nociceptor neurons play a crucial role in maintaining the body's homeostasis by detecting and responding to potential environmental dangers. However, this function can be detrimental during allergic reactions, as vagal nociceptors contribute to immune cell infiltration, bronchial hypersensitivity, and mucus imbalance in addition to causing pain and coughing. Despite this, the specific mechanisms by which nociceptors acquire pro-inflammatory characteristics during allergic reactions are not yet fully understood. In this study, we investigate the changes in the molecular profile of airway nociceptor neurons during allergic airway inflammation and identify the signals driving such reprogramming. Using retrograde tracing and lineage reporting, we identify a specific class of inflammatory vagal nociceptor neurons that exclusively innervate the airways. In the ovalbumin mouse model of allergic airway inflammation, these neurons undergo significant reprogramming characterized by the upregulation of the neuropeptide Y (NPY) receptor Npy1r. A screening of cytokines and neurotrophins reveals that interleukin 1β (IL-1β), IL-13, and brain-derived neurotrophic factor (BDNF) drive part of this reprogramming. IL-13 triggers Npy1r overexpression in nociceptors via the JAK/STAT6 pathway. In parallel, NPY is released into the bronchoalveolar fluid of asthmatic mice, which limits the excitability of nociceptor neurons. Single-cell RNA sequencing of lung immune cells reveals that a cell-specific knockout of NPY1R in nociceptor neurons in asthmatic mice altered T cell infiltration. Opposite findings are observed in asthmatic mice in which nociceptor neurons are chemically ablated. In summary, allergic airway inflammation reprograms airway nociceptor neurons to acquire a pro-inflammatory phenotype, while a compensatory mechanism involving NPY1R limits the activity of nociceptor neurons.
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Affiliation(s)
- Theo Crosson
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada
| | - Shreyas Bhat
- Centre Interdisciplinaire sur le Cerveau et l'Apprentissage, Université de Montréal, Montreal, QC, Canada; Département de Physique, Université de Montréal, Montreal, QC, Canada
| | - Jo-Chiao Wang
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada
| | - Clara Salaun
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada
| | - Eleanne Fontaine
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada
| | - Katiane Roversi
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada
| | - Herbert Herzog
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Moutih Rafei
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada
| | - Rikard Blunck
- Centre Interdisciplinaire sur le Cerveau et l'Apprentissage, Université de Montréal, Montreal, QC, Canada; Département de Physique, Université de Montréal, Montreal, QC, Canada
| | - Sebastien Talbot
- Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
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Branyiczky MK, Towheed S, Torres T, Vender R. A systematic review of recent randomized controlled trials for palmoplantar pustulosis. J DERMATOL TREAT 2024; 35:2414048. [PMID: 39389576 DOI: 10.1080/09546634.2024.2414048] [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: 09/04/2024] [Accepted: 10/03/2024] [Indexed: 10/12/2024]
Abstract
Background: Palmoplantar pustulosis (PPP) is a chronic inflammatory condition, that leads to significant functional impairment and reduced quality of life. Despite its low incidence, treatment options are diverse and often ineffective, necessitating a review of recent therapeutic advances. Objective: This review aims to evaluate the efficacy and safety of recent therapeutic options for the treatment of PPP, focusing on phototherapy, systemic therapies, and biologics. Materials and methods: A systematic literature search identified 13 studies evaluating phototherapy and systemic therapies, including biologics. Inclusion criteria focused on randomized controlled trials with participants diagnosed with PPP. Results: Phototherapy showed success: excimer laser demonstrated high efficacy for severe disease [PPP Area and Severity Index (PPPASI)-75 of 95.0%], while psoralen plus ultraviolet A therapy with retinoids or fumaric acid esters worked well in milder disease (PPPASI-90 of 90.0 and 81.8%, respectively). Evidence supports the efficacy and safety of guselkumab, brodalumab, and apremilast over a range of disease severity (PPPASI-50 ranged from 57.4 to 78.3% at week 16). Agents including anakinra, secukinumab, spesolimab, and RIST4721 (primary outcomes not achieved) may not be first-line treatments. By targeting multiple inflammatory pathways in PPP, JAK inhibitors may be more effective than biologics in treating PPP; however, more research is needed to confirm their safety and appropriate use. Conclusions: Multiple new treatments exist for PPP with promising results, however longer-term studies with standardized outcome reporting are needed to determine optimal treatment strategies and their comparative efficacy.
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Affiliation(s)
| | - Shahnawaz Towheed
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Canada
| | - Tiago Torres
- Department of Dermatology, CAC ICBAS-CHP-Centro Académico Clínico ICBAS-CHP, Porto, Portugal
- UMIB-Unit for Multidisciplinary Research in Biomedicine, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
| | - Ronald Vender
- Division of Dermatology, McMaster University, Hamilton, Canada
- Dermatrials Research Inc., Hamilton, Canada
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Chen J, Xue X, Wang Z, Liu H, Zhang F. Genetic analysis of different subtypes of aseptic pustulosis in the Chinese population. Clin Exp Dermatol 2024; 49:1217-1226. [PMID: 38651209 DOI: 10.1093/ced/llae144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 03/06/2024] [Accepted: 04/16/2024] [Indexed: 04/25/2024]
Abstract
Aseptic pustulosis involves inflammatory skin conditions with nonbacterial pustules on erythema, accompanied by neutrophil and eosinophil infiltration in the epidermis. Dysregulation of the interleukin (IL)-36 pathway leads to neutrophil aggregation and pustule formation. Variants in IL36RN, CARD14, AP1S3, MPO, SERPINA3 and BTN3A3 have been identified in generalized pustular psoriasis (GPP) in the past. Some patients with acrodermatitis continua of Hallopeau (ACH), palmoplantar pustulosis and acute generalized exanthematous pustulosis (AGEP) also exhibit mutations in IL36RN, CARD14 and AP1S3, albeit with regional and population-specific variations. This study aims to explore a shared genetic foundation among those with aseptic pustulosis. We performed Sanger sequencing on six genes in 126 patients with aseptic pustulosis. Genetic analysis identified IL36RN variants strongly associated with ACH, AGEP and subcorneal pustular dermatosis (SPD). Immunohistochemistry revealed elevated inflammatory cytokines in all subtypes. This study establishes a significant association between IL36RN variants and ACH, AGEP and SPD, emphasizing the IL-1/IL-36-chemokine-neutrophil axis as a common pathogenic mechanism. Targeting this axis holds promise for therapeutic interventions for aseptic pustulosis.
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Affiliation(s)
- Jing Chen
- Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xiaotong Xue
- Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zhenzhen Wang
- Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Hong Liu
- Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Furen Zhang
- Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
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Crosson T, Bhat S, Wang JC, Salaun C, Fontaine E, Roversi K, Herzog H, Rafei M, Blunck R, Talbot S. Cytokines reprogram airway sensory neurons in asthma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.01.26.525731. [PMID: 39345572 PMCID: PMC11429693 DOI: 10.1101/2023.01.26.525731] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Nociceptor neurons play a crucial role in maintaining the body's homeostasis by detecting and responding to potential dangers in the environment. However, this function can be detrimental during allergic reactions, since vagal nociceptors can contribute to immune cell infiltration, bronchial hypersensitivity, and mucus imbalance, in addition to causing pain and coughing. Despite this, the specific mechanisms by which nociceptors acquire pro-inflammatory characteristics during allergic reactions are not yet fully understood. In this study, we aimed to investigate the molecular profile of airway nociceptor neurons during allergic airway inflammation and identify the signals driving such reprogramming. Using retrograde tracing and lineage reporting, we identified a unique class of inflammatory vagal nociceptor neurons that exclusively innervate the airways. In the ovalbumin mouse model of airway inflammation, these neurons undergo significant reprogramming characterized by the upregulation of the NPY receptor Npy1r. A screening of cytokines and neurotrophins revealed that IL-1β, IL-13 and BDNF drive part of this reprogramming. IL-13 triggered Npy1r overexpression in nociceptors via the JAK/STAT6 pathway. In parallel, sympathetic neurons and macrophages release NPY in the bronchoalveolar fluid of asthmatic mice, which limits the excitability of nociceptor neurons. Single-cell RNA sequencing of lung immune cells has revealed that a cell-specific knockout of Npy1r in nociceptor neurons in asthmatic mice leads to an increase in airway inflammation mediated by T cells. Opposite findings were observed in asthmatic mice in which nociceptor neurons were chemically ablated. In summary, allergic airway inflammation reprograms airway nociceptor neurons to acquire a pro-inflammatory phenotype, while a compensatory mechanism involving NPY1R limits nociceptor neurons' activity.
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Affiliation(s)
- Théo Crosson
- Département de Pharmacologie et Physiologie, Université de Montréal, Canada
| | - Shreyas Bhat
- Centre Interdisciplinaire sur le Cerveau et l’Apprentissage, Université de Montréal, Canada
- Département de Physique, Université de Montréal, Canada
| | - Jo-Chiao Wang
- Département de Pharmacologie et Physiologie, Université de Montréal, Canada
| | - Clara Salaun
- Département de Pharmacologie et Physiologie, Université de Montréal, Canada
| | - Eleanne Fontaine
- Département de Pharmacologie et Physiologie, Université de Montréal, Canada
| | - Katiane Roversi
- Département de Pharmacologie et Physiologie, Université de Montréal, Canada
| | | | - Moutih Rafei
- Département de Pharmacologie et Physiologie, Université de Montréal, Canada
| | - Rikard Blunck
- Centre Interdisciplinaire sur le Cerveau et l’Apprentissage, Université de Montréal, Canada
- Département de Physique, Université de Montréal, Canada
| | - Sebastien Talbot
- Department of Physiology and Pharmacology, Karolinska Institutet. Sweden
- Department of Biomedical and Molecular Sciences, Queen’s University. Canada
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9
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Kim SR, Choi YG, Jo SJ. Effect of smoking cessation on psoriasis vulgaris, palmoplantar pustulosis and generalized pustular psoriasis. Br J Dermatol 2024; 191:225-232. [PMID: 38534203 DOI: 10.1093/bjd/ljae130] [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: 12/26/2023] [Revised: 02/25/2024] [Accepted: 03/21/2024] [Indexed: 03/28/2024]
Abstract
BACKGROUND Smoking is a known risk factor for psoriasis; however, the impact of smoking cessation on psoriasis has seldom been evaluated. OBJECTIVES We aimed to examine the effects of smoking cessation on the development of psoriasis vulgaris (PsV), palmoplantar pustulosis (PPP) and generalized pustular psoriasis (GPP). METHODS Using the Korean National Health Insurance Service database, we retrospectively compiled a cohort of 5 784 973 participants without psoriasis, analysed their changes in smoking status from 2004 to 2007 and followed up new cases of psoriasis until 2021. The psoriasis risks were compared with those of sustained smokers, smoking quitters, sustained ex-smokers and never smokers using multivariate Cox proportional hazard models. RESULTS The mean age of the participants was 47.1 years (SD 13.5) and 3 092 426 (53.5%) were male. During 77 990 688 person-years, 67 364 psoriasis cases were identified. Compared with sustained smokers, smoking quitters showed a reduced risk of developing psoriasis [adjusted hazard ratio (aHR) 0.91; 95% confidence interval (CI) 0.87-0.95], specifically PsV (aHR 0.92; 95% CI 0.88-0.97) and PPP (aHR 0.71; 95% CI 0.63-0.79). The reduction in risk due to smoking cessation was more prominent in sustained ex-smokers (psoriasis: aHR 0.77, 95% CI 0.74-0.79; PsV: aHR 0.76, 95% CI 0.73-0.79; PPP: aHR 0.56, 95% CI 0.51-0.61; GPP: aHR 0.64; 95% CI 0.52-0.78). When conducting sensitivity analyses to address the potential for changes in smoking habits after 2007, the results and trends were consistent with the main findings, and a more pronounced significance was observed. CONCLUSIONS Compared with continuous smoking, smoking cessation was associated with a decreased risk of developing psoriasis. The risk-reducing effect of smoking cessation was more pronounced in those maintaining a smoke-free status. Smoking cessation and the maintenance of a smoke-free status should be encouraged to prevent the development of psoriasis and all other smoking-related diseases.
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Affiliation(s)
- Seong Rae Kim
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Dermatology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Young-Geun Choi
- Department of Mathematics Education, Sungkyunkwan University, Seoul, Republic of Korea
| | - Seong Jin Jo
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Dermatology, Seoul National University Hospital, Seoul, Republic of Korea
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Cramer N, Buhl T, Schön MP, Mössner R. Erste Episode einer generalisierten pustulösen Psoriasis oder akute generalisierte exanthematische Pustulose? Eine Fallstudie. J Dtsch Dermatol Ges 2024; 22:693-695. [PMID: 38730514 DOI: 10.1111/ddg.15332_g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 11/15/2023] [Indexed: 05/13/2024]
Affiliation(s)
- Neda Cramer
- Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Göttingen
| | - Timo Buhl
- Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Göttingen
| | - Michael P Schön
- Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Göttingen
| | - Rotraut Mössner
- Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Göttingen
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11
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Qing M, Yang D, Shang Q, Li W, Zhou Y, Xu H, Chen Q. Humoral immune disorders affect clinical outcomes of oral lichen planus. Oral Dis 2024; 30:2337-2346. [PMID: 37392455 DOI: 10.1111/odi.14667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 07/03/2023]
Abstract
OBJECTIVES The molecular characteristics of oral lichen planus (OLP) are still unclear, and it is not possible to distinguish the clinical outcome of OLP patients in a short period of time for follow-up. Here, we investigate the molecular characteristics of lesions in patients with stable lichen planus (SOLP) and recalcitrant erosive oral lichen planus (REOLP). METHODS Our clinical follow-up cohort was split into SOLP and REOLP groups based on the follow-up clinical data. The core modules associated with the clinical information were identified by weighted gene co-expression network analysis (WGCNA). The OLP cohort samples were divided into two groups by molecular typing, and a prediction model for OLP was created by training neural networks with the neuralnet package. RESULTS We screened 546 genes in five modules. After doing a molecular type of OLP, it was determined that B cells might have a significant impact on the clinical outcome of OLP. In addition, by means of machine learning, a prediction model was developed to predict the clinical regression of OLP with greater accuracy than the existing clinical diagnostic. CONCLUSIONS Our study revealed humoral immune disorders may make an important contribution to the clinical outcome of OLP.
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Affiliation(s)
- Maofeng Qing
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Stomatology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dan Yang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Qianhui Shang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Weiqi Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yu Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Hao Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Qianming Chen
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Affiliated Stomatology Hospital, Zhejiang University School of Stomatology, Hangzhou, China
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12
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Cramer N, Buhl T, Schön MP, Mössner R. First episode of generalized pustular psoriasis or acute generalized exanthematous pustulosis? A case study. J Dtsch Dermatol Ges 2024; 22:693-695. [PMID: 38487968 DOI: 10.1111/ddg.15332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 11/15/2023] [Indexed: 05/12/2024]
Affiliation(s)
- Neda Cramer
- Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany
| | - Timo Buhl
- Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany
| | - Michael P Schön
- Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany
| | - Rotraut Mössner
- Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany
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13
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Ahmad F, Alam MA, Ansari AW, Jochebeth A, Leo R, Al-Abdulla MN, Al-Khawaga S, AlHammadi A, Al-Malki A, Al Naama K, Ahmad A, Buddenkotte J, Steinhoff M. Emerging Role of the IL-36/IL-36R Axis in Multiple Inflammatory Skin Diseases. J Invest Dermatol 2024; 144:206-224. [PMID: 38189700 DOI: 10.1016/j.jid.2023.11.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 10/26/2023] [Accepted: 11/14/2023] [Indexed: 01/09/2024]
Abstract
IL-36 is a most recent member of the IL-1 cytokine family, primarily expressed at barrier sites of the body such as the skin, lungs, and intestine. It plays a vital role in inflammation and is implicated in the development of various cutaneous; intestinal; and pulmonary disorders, including psoriasis, inflammatory bowel disease, and chronic obstructive pulmonary disease. IL-36 comprises 4 isoforms: the proinflammatory IL-36α, IL-36β, and IL-36γ and the anti-inflammatory IL-36R antagonist. An imbalance between proinflammatory and anti-inflammatory IL-36 isoforms can contribute to the inflammatory fate of cells and tissues. IL-36 cytokines signal through an IL-36R heterodimer mediating their function through canonical signaling cacade, including the NF-B pathway. Prominent for its role in psoriasis, IL-36 has recently been associated with disease mechanisms in atopic dermatitis, hidradenitis suppurativa, neutrophilic dermatoses, autoimmune blistering disease, and Netherton syndrome. The major cutaneous source of IL-36 cytokines is keratinocytes, pointing to its role in the communication between the epidermis, innate (neutrophils, dendritic cells) immune system, and adaptive (T helper [Th]1 cells, Th17) immune system. Thus, cutaneous IL-36 signaling is crucial for the immunopathological outcome of various skin diseases. Consequently, the IL-36/IL-36R axis has recently been recognized as a promising drug target for the treatment of inflammatory disorders beyond psoriasis. This review summarizes the current update on IL-36 cytokines in inflammatory skin diseases.
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Affiliation(s)
- Fareed Ahmad
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Majid Ali Alam
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Abdul Wahid Ansari
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Anh Jochebeth
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Rari Leo
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | | | - Sara Al-Khawaga
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar
| | - Ayda AlHammadi
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar
| | - Aysha Al-Malki
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar
| | - Khalifa Al Naama
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar
| | - Aamir Ahmad
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Jörg Buddenkotte
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
| | - Martin Steinhoff
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Medical School, Qatar University, Doha, Qatar; Weill Cornell Medicine, Weill Cornell University, New York, New York, USA; Weill Cornell Medicine-Qatar, Doha, Qatar.
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14
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Lan Y, Wu X, Zhong X, Song P, Liu L, Liu Y, Ai X, Han C, Zhang Z. Increased neutrophil-derived IL-17A identified in generalized pustular psoriasis. Exp Dermatol 2024; 33:e15026. [PMID: 38414093 DOI: 10.1111/exd.15026] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 01/18/2024] [Accepted: 01/21/2024] [Indexed: 02/29/2024]
Abstract
Generalized pustular psoriasis (GPP) is considered to be a distinct clinical entity from psoriasis vulgaris (PV), with different clinical and histological manifestations. The pathogenesis of GPP has not been thoroughly elucidated, especially in those patients lacking interleukin (IL)36RN. In present study, we performed RNA sequence analysis on skin lesions from 10 GPP patients (4 with and 6 without IL36RN mutation) and 10 PV patients without IL36RN mutation. Compared with PV, significantly overexpressed genes in GPP patients were enriched in IL-17 signalling pathway (MMP1, MMP3, DEFB4A and DEFB4B, etc.) and associated with neutrophil infiltration (MMP1, MMP3, ANXA and SERPINB, etc.). GPP with IL36RN mutations evidenced WNT11 upregulation and IL36RN downregulation in comparison to those GPP without IL36RN mutations. The expression of IL-17A/IL-36 in skin or serum and the origin of IL-17A in skin were also investigated. IL-17A expression in skin was significantly higher in GPP than PV patients, whereas, there were no differences in skin IL-36α/IL-36γ/IL-36RA or serum IL-17A/IL-36α/IL-36γ between GPP than PV. Besides, double immunofluorescence staining of MPO/IL-17A or CD3/IL-17A further confirmed that the majority of IL-17A in GPP skin was derived from neutrophils, but not T cells. These data emphasized the role of neutrophil-derived IL-17A in the pathogenesis of GPP with or without IL36RN mutations. Targeting neutrophil-derived IL-17A might be a promising treatment for GPP.
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Affiliation(s)
- Yu Lan
- Department of Dermatology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Xiaoyan Wu
- Department of Dermatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Xinyu Zhong
- Department of Dermatology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Pengfei Song
- Department of Dermatology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Leying Liu
- Department of Dermatology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Yuhua Liu
- Department of Dermatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Xuechen Ai
- Department of Dermatology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Changxu Han
- Department of Dermatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Zhenying Zhang
- Department of Dermatology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
- Department of Dermatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
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15
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Fang ZX, Chen WJ, Wu Z, Hou YY, Lan YZ, Wu HT, Liu J. Inflammatory response in gastrointestinal cancers: Overview of six transmembrane epithelial antigens of the prostate in pathophysiology and clinical implications. World J Clin Oncol 2024; 15:9-22. [PMID: 38292664 PMCID: PMC10823946 DOI: 10.5306/wjco.v15.i1.9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/24/2023] [Accepted: 12/19/2023] [Indexed: 01/23/2024] Open
Abstract
Chronic inflammation is known to increase the risk of gastrointestinal cancers (GICs), the common solid tumors worldwide. Precancerous lesions, such as chronic atrophic inflammation and ulcers, are related to inflammatory responses in vivo and likely to occur in hyperplasia and tumorigenesis. Unfortunately, due to the lack of effective therapeutic targets, the prognosis of patients with GICs is still unsatisfactory. Interestingly, it is found that six transmembrane epithelial antigens of the prostate (STEAPs), a group of metal reductases, are significantly associated with the progression of malignancies, playing a crucial role in systemic metabolic homeostasis and inflammatory responses. The structure and functions of STEAPs suggest that they are closely related to intracellular oxidative stress, responding to inflammatory reactions. Under the imbalance status of abnormal oxidative stress, STEAP members are involved in cell transformation and the development of GICs by inhibiting or activating inflammatory process. This review focuses on STEAPs in GICs along with exploring their potential molecular regulatory mechanisms, with an aim to provide a theoretical basis for diagnosis and treatment strategies for patients suffering from these types of cancers.
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Affiliation(s)
- Ze-Xuan Fang
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Zheng Wu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yan-Yu Hou
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yang-Zheng Lan
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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16
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Fu D, Zhang X, Zhou Y, Hu S. A novel prognostic signature and therapy guidance for hepatocellular carcinoma based on STEAP family. BMC Med Genomics 2024; 17:16. [PMID: 38191397 PMCID: PMC10775544 DOI: 10.1186/s12920-023-01789-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 12/26/2023] [Indexed: 01/10/2024] Open
Abstract
BACKGROUND The six-transmembrane epithelial antigen of prostate (STEAP) family members are known to be involved in various tumor-related biological processes and showed its huge potential role in tumor immunotherapy. METHODS Biological differences were investigated through Gene set enrichment analysis (GSEA) and tumor microenvironment analysis by CIBERSORT. Tumor mutation burden (TMB), immunotherapy response and chemotherapeutic drugs sensitivity were estimated in R. RESULTS We established a prognostic signature with the formula: risk score = STEAP1 × 0.3994 + STEAP4 × (- 0.7596), which had a favorable concordance with the prediction. The high-risk group were enriched in cell cycle and RNA and protein synthesis related pathways, while the low-risk group were enriched in complement and metabolic related pathways. And the risk score was significantly correlated with immune cell infiltration. Most notably, the patients in the low-risk group were characterized with increased TMB and decreased tumor immune dysfunction and exclusion (TIDE) score, indicating that these patients showed better immune checkpoint blockade response. Meanwhile, we found the patients with high-risk were more sensitive to some drugs related to cell cycle and apoptosis. CONCLUSIONS The novel signature based on STEAPs may be effective indicators for predicting prognosis, and provides corresponding clinical treatment recommendations for HCC patients based on this classification.
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Affiliation(s)
- Dongxue Fu
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xian Zhang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No.1 South Baixiang Street, Ouhai District, Wenzhou, Zhejiang, 325000, China
| | - Yi Zhou
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No.1 South Baixiang Street, Ouhai District, Wenzhou, Zhejiang, 325000, China
| | - Shanshan Hu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, No.1 South Baixiang Street, Ouhai District, Wenzhou, Zhejiang, 325000, China.
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17
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Zhang C, Sheng M, Lv J, Cao Y, Chen D, Jia L, Sun Y, Ren Y, Li L, Weng Y, Yu W. Single-cell analysis reveals the immune heterogeneity and interactions in lungs undergoing hepatic ischemia-reperfusion. Int Immunopharmacol 2023; 124:111043. [PMID: 37844464 DOI: 10.1016/j.intimp.2023.111043] [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: 07/12/2023] [Revised: 10/02/2023] [Accepted: 10/08/2023] [Indexed: 10/18/2023]
Abstract
Hepatic ischemia-reperfusion IR (HIR) is an unavoidable pathophysiological process during liver transplantation, resulting in systematic sterile inflammation and remote organ injury. Acute lung injury (ALI) is a serious complication after liver transplantation with high postoperative morbidity and mortality. However, the underlying mechanism is still unclear. To assess the phenotype and plasticity of various cell types in the lung tissue microenvironment after HIR at the single-cell level, single-cell RNA sequencing (scRNA-seq) was performed using the lungs from HIR-induced mice. In our results, we identified 23 cell types in the lungs after HIR and found that this highly complex ecosystem was formed by subpopulations of bone marrow-derived cells that signaled each other and mediated inflammatory responses in different states and different intervals. We described the unique transcriptional profiles of lung cell clusters and discovered two novel cell subtypes (Tspo+Endothelial cells and Vcan+ monocytes), as well as the endothelial cell-immune cell and immune cell-T cell clusters interactome. In addition, we found that S100 calcium binding protein (S100a8/a9), specifically and highly expressed in immune cell clusters of lung tissues and exhibited detrimental effects. Finally, the cellular landscape of the lung tissues after HIR was established, highlighting the heterogeneity and cellular interactions between major immune cells in HIR-induced lungs. Our findings provided new insights into the mechanisms of HIR-induced ALI and offered potential therapeutic target to prevent ALI after liver transplantation.
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Affiliation(s)
- Chen Zhang
- The First Central Clinical School, Tianjin Medical University, Tianjin 300052, China; Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Mingwei Sheng
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Jingshu Lv
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Yingli Cao
- School of Medical, Nankai University, Tianjin 300071, China
| | - Dapeng Chen
- The First Central Clinical School, Tianjin Medical University, Tianjin 300052, China
| | - Lili Jia
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Ying Sun
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Yinghui Ren
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Lian Li
- College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Yiqi Weng
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Wenli Yu
- The First Central Clinical School, Tianjin Medical University, Tianjin 300052, China; Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China.
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18
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Terui T, Okubo Y, Kobayashi S, Sano S, Morita A, Imafuku S, Tada Y, Abe M, Yaguchi M, Uehara N, Handa T, Tanaka M, Zhang W, Paris M, Murakami M. Efficacy and Safety of Apremilast for the Treatment of Japanese Patients with Palmoplantar Pustulosis: Results from a Phase 2, Randomized, Placebo-Controlled Study. Am J Clin Dermatol 2023; 24:837-847. [PMID: 37233897 PMCID: PMC10213585 DOI: 10.1007/s40257-023-00788-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2023] [Indexed: 05/27/2023]
Abstract
BACKGROUND Palmoplantar pustulosis (PPP) is a pruritic, painful, recurrent, and chronic dermatitis with limited therapeutic options. OBJECTIVE To evaluate the efficacy and safety of apremilast for the treatment of Japanese patients with PPP and inadequate response to topical treatment. METHODS This phase 2, randomized, double-blind, placebo-controlled study enrolled patients with Palmoplantar Pustulosis Area and Severity Index (PPPASI) total score ≥ 12 and moderate or severe pustules/vesicles on the palm or sole (PPPASI pustule/vesicle severity score ≥ 2) at screening and baseline with an inadequate response to topical treatment. Patients were randomized (1:1) to apremilast 30 mg twice daily or placebo for 16 weeks, followed by a 16-week extension phase during which all patients received apremilast. The primary endpoint was achievement of PPPASI-50 response (≥ 50% improvement from baseline in PPPASI). Key secondary endpoints included change from baseline in PPPASI total score, Palmoplantar Pustulosis Severity Index (PPSI), and patient's visual analog scale (VAS) for PPP symptoms (pruritus and discomfort/pain). RESULTS A total of 90 patients were randomized (apremilast: 46; placebo: 44). A significantly greater proportion of patients achieved PPPASI-50 at week 16 with apremilast versus placebo (P = 0.0003). Patients receiving apremilast showed greater improvement in PPPASI at week 16 versus placebo (nominal P = 0.0013), as well as PPSI and patient-reported pruritus and discomfort/pain (nominal P ≤ 0.001 for all). Improvements were sustained through week 32 with apremilast treatment. The most common treatment-emergent adverse events included diarrhea, abdominal discomfort, headache, and nausea. CONCLUSIONS Apremilast treatment demonstrated greater improvements in disease severity and patient-reported symptoms versus placebo at week 16 in Japanese patients with PPP with sustained improvements through week 32. No new safety signals were observed. CLINICALTRIALS GOV: NCT04057937.
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Affiliation(s)
- Tadashi Terui
- Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi, Tokyo, 173-8610, Japan.
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19
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Zou X, Liu C, Huang Z, Xiang S, Li K, Yuan Y, Hao Y, Zhou F. Inhibition of STEAP1 ameliorates inflammation and ferroptosis of acute lung injury caused by sepsis in LPS-induced human pulmonary microvascular endothelial cells. Mol Biol Rep 2023:10.1007/s11033-023-08403-7. [PMID: 37209327 DOI: 10.1007/s11033-023-08403-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 03/23/2023] [Indexed: 05/22/2023]
Abstract
BACKGROUND Ferroptosis plays an important part in Acute lung injury (ALI) caused by sepsis. The six-transmembrane epithelial antigen of the prostate 1 (STEAP1) has potential effects on iron metabolism and inflammation but reports on its function in ferroptosis and sepsis-caused ALI are lacking. Here we explored the role of STEAP1 in sepsis-caused ALI and the possible mechanisms. METHODS AND RESULTS Lipopolysaccharide (LPS) was added to human pulmonary microvascular endothelial cells (HPMECs) to form the sepsis-caused ALI model in vitro. The Cecal ligation and puncture (CLP) experiment was performed on C57/B6J mice to form the sepsis-caused ALI model in vivo. The effect of STEAP1 on inflammation was investigated by PCR, ELISA, and Western blot for the inflammatory factors and adhesion molecular. The reactive oxygen species (ROS) levels were detected by immunofluorescence. The effect of STEAP1 on ferroptosis was investigated by detecting malondialdehyde (MDA) levels, glutathione (GSH) levels, Fe2+ levels, cell viability, and mitochondrial morphology. Our findings suggested that STEAP1 expression was increased in the sepsis-induced ALI models. Inhibition of STEAP1 decreased the inflammatory response and ROS production as well as MDA levels but increased the levels of Nrf2 and GSH. Meanwhile, inhibition of STEAP1 improved cell viability and restored mitochondrial morphology. Western Blot results showed that inhibition of STEAP1 could affect the SLC7A11/GPX4 axis. CONCLUSION Inhibition of STEAP1 may be valuable for pulmonary endothelial protection in lung injury caused by sepsis.
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Affiliation(s)
- Xuan Zou
- Department of Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Chang Liu
- Department of Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Zuotian Huang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Song Xiang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Kaili Li
- Department of Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Yuan Yuan
- Department of Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Yingting Hao
- Department of Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Fachun Zhou
- Department of Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China.
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20
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Rocha SM, Nascimento D, Coelho RS, Cardoso AM, Passarinha LA, Socorro S, Maia CJ. STEAP1 Knockdown Decreases the Sensitivity of Prostate Cancer Cells to Paclitaxel, Docetaxel and Cabazitaxel. Int J Mol Sci 2023; 24:6643. [PMID: 37047621 PMCID: PMC10095014 DOI: 10.3390/ijms24076643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 03/27/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
The Six Transmembrane Epithelial Antigen of the Prostate 1 (STEAP1) protein has been indicated as an overexpressed oncoprotein in prostate cancer (PCa), associated with tumor progression and aggressiveness. Taxane-based antineoplastic drugs such as paclitaxel, docetaxel, or cabazitaxel, have been investigated in PCa treatment, namely for the development of combined therapies with the improvement of therapeutic effectiveness. This study aimed to evaluate the expression of STEAP1 in response to taxane-based drugs and assess whether the sensitivity of PCa cells to treatment with paclitaxel, docetaxel, or cabazitaxel may change when the STEAP1 gene is silenced. Thus, wild-type and STEAP1 knockdown LNCaP and C4-2B cells were exposed to paclitaxel, docetaxel or cabazitaxel, and STEAP1 expression, cell viability, and survival pathways were evaluated. The results obtained showed that STEAP1 knockdown or taxane-based drugs treatment significantly reduced the viability and survival of PCa cells. Relatively to the expression of proliferation markers and apoptosis regulators, LNCaP cells showed a reduced proliferation, whereas apoptosis was increased. However, the effect of paclitaxel, docetaxel, or cabazitaxel treatment was reversed when combined with STEAP1 knockdown. Besides, these chemotherapeutic drugs may stimulate the cell growth of PCa cells knocked down for STEAP1. In conclusion, this study demonstrated that STEAP1 expression levels might influence the response of PCa cells to chemotherapeutics drugs, indicating that the use of paclitaxel, docetaxel, or cabazitaxel may lead to harmful effects in PCa cells with decreased expression of STEAP1.
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Affiliation(s)
- Sandra M. Rocha
- CICS-UBI–Health Sciences Research Center, Universidade da Beira Interior, 6201-506 Covilhã, Portugal; (S.M.R.)
| | - Daniel Nascimento
- CICS-UBI–Health Sciences Research Center, Universidade da Beira Interior, 6201-506 Covilhã, Portugal; (S.M.R.)
| | - Rafaella S. Coelho
- CICS-UBI–Health Sciences Research Center, Universidade da Beira Interior, 6201-506 Covilhã, Portugal; (S.M.R.)
| | - Ana Margarida Cardoso
- CICS-UBI–Health Sciences Research Center, Universidade da Beira Interior, 6201-506 Covilhã, Portugal; (S.M.R.)
| | - Luís A. Passarinha
- CICS-UBI–Health Sciences Research Center, Universidade da Beira Interior, 6201-506 Covilhã, Portugal; (S.M.R.)
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2819-516 Caparica, Portugal
- UCIBIO–Applied Molecular Biosciences Unit, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2819-516 Caparica, Portugal
- Laboratório de Fármaco-Toxicologia-UBIMedical, Universidade da Beira Interior, 6201-284 Covilhã, Portugal
| | - Sílvia Socorro
- CICS-UBI–Health Sciences Research Center, Universidade da Beira Interior, 6201-506 Covilhã, Portugal; (S.M.R.)
- C4-UBI—Cloud Computing Competence Center, Universidade da Beira Interior, 6200-501 Covilhã, Portugal
| | - Cláudio J. Maia
- CICS-UBI–Health Sciences Research Center, Universidade da Beira Interior, 6201-506 Covilhã, Portugal; (S.M.R.)
- C4-UBI—Cloud Computing Competence Center, Universidade da Beira Interior, 6200-501 Covilhã, Portugal
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Understanding the Pathogenesis of Generalized Pustular Psoriasis Based on Molecular Genetics and Immunopathology. INTERNATIONAL JOURNAL OF DERMATOLOGY AND VENEREOLOGY 2022. [DOI: 10.1097/jd9.0000000000000277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Bachelez H, Barker J, Burden AD, Navarini AA, Krueger JG. Generalized pustular psoriasis is a disease distinct from psoriasis vulgaris: evidence and expert opinion. Expert Rev Clin Immunol 2022; 18:1033-1047. [PMID: 36062811 DOI: 10.1080/1744666x.2022.2116003] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/18/2022] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Generalized pustular psoriasis (GPP) is a rare, severe, clinically heterogeneous disease characterized by flares of widespread, noninfectious, macroscopically visible pustules that occur with or without systemic inflammation, and are associated with significant morbidity and mortality. Historically, GPP has been classified as a variant of psoriasis vulgaris (PV, or plaque psoriasis); however, accumulating evidence indicates that these are distinct conditions, requiring different treatment approaches. AREAS COVERED In this perspective article we review evidence that supports the classification of GPP as distinct from PV. EXPERT OPINION The histopathologic and clinical appearance of GPP is distinct from that of PV and fundamental differences exist between the two conditions in terms of genetic causes and expression-related mechanisms of disease development. GPP results from dysregulation of the innate immune system, with disruption of the interleukin (IL)-36 inflammatory pathway, induction of inflammatory keratinocyte responses, and recruitment of neutrophils. PV is driven by the adaptive immune system, with a key role played by IL-17. Considering GPP as a separate disease will enable greater focus on its specific pathogenesis and the needs of patients. Many treatments for PV have insufficient efficacy in GPP and a therapeutic approach developed specifically for GPP might lead to better patient outcomes.
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Affiliation(s)
- Hervé Bachelez
- Service de Dermatologie, Assistance Publique-Hôpitaux de Paris Hôpital Saint-Louis, Paris, France, and INSERM Unité 1163, Imagine Institute of Genetic Diseases, Université Paris Cité, Paris, France
| | - Jonathan Barker
- St John's Institute of Dermatology, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - A David Burden
- Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, UK
| | | | - James G Krueger
- Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA
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23
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Kura MM, Sodhi A, Sajgane A, Karande A. Anti CD-6 Monoclonal Antibodies in the Management of Generalised Pustular Psoriasis. Indian J Dermatol 2022; 67:568-572. [PMID: 36865872 PMCID: PMC9971756 DOI: 10.4103/ijd.ijd_180_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023] Open
Abstract
Generalised pustular psoriasis (GPP) is an uncommon, severe, life-threatening variant of psoriasis requiring careful therapeutic approach. Conventional treatment modalities have unsatisfactory outcomes, poor side effect profiles and toxicities that have led to an emerging use of biological therapies. Itolizumab, an anti-CD-6 humanised monoclonal IgG1 antibody, is approved for the management of chronic plaque psoriasis in India. We share our experience of using this drug in three cases of GPP that were failing conventional therapies. Its upstream effect on co-stimulatory pathway in disease pathogenesis is the postulated mechanism. Our experience warrants further large-scale exploration of the role of itolizumab in the management of GPP, which would benefit this severely affected population of patients. Although the definite pathogenesis of GPP is unknown fully, molecules blocking CD-6, which plays a role in the interaction between T cells and antigen-presenting cells (APCs), are expected as new promising treatment options for GPP.
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Affiliation(s)
- Mahendra M. Kura
- From the Department of Dermatology, Venereology and Leprosy, Grant Government Medical College, Sir JJ Group of Hospitals, Mumbai, Maharashtra, India
| | - Anmol Sodhi
- From the Department of Dermatology, Venereology and Leprosy, Grant Government Medical College, Sir JJ Group of Hospitals, Mumbai, Maharashtra, India
| | - Avinash Sajgane
- From the Department of Dermatology, Venereology and Leprosy, Grant Government Medical College, Sir JJ Group of Hospitals, Mumbai, Maharashtra, India
| | - Ashish Karande
- From the Department of Dermatology, Venereology and Leprosy, Grant Government Medical College, Sir JJ Group of Hospitals, Mumbai, Maharashtra, India
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24
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Sachen KL, Arnold Greving CN, Towne JE. Role of IL-36 cytokines in psoriasis and other inflammatory skin conditions. Cytokine 2022; 156:155897. [DOI: 10.1016/j.cyto.2022.155897] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 03/29/2022] [Accepted: 04/22/2022] [Indexed: 12/15/2022]
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25
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Comprehensive Landscape of STEAP Family Members Expression in Human Cancers: Unraveling the Potential Usefulness in Clinical Practice Using Integrated Bioinformatics Analysis. DATA 2022. [DOI: 10.3390/data7050064] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
The human Six-Transmembrane Epithelial Antigen of the Prostate (STEAP) family comprises STEAP1-4. Several studies have pointed out STEAP proteins as putative biomarkers, as well as therapeutic targets in several types of human cancers, particularly in prostate cancer. However, the relationships and significance of the expression pattern of STEAP1-4 in cancer cases are barely known. Herein, the Oncomine database and cBioPortal platform were selected to predict the differential expression levels of STEAP members and clinical prognosis. The most common expression pattern observed was the combination of the over- and underexpression of distinct STEAP genes, but cervical and gastric cancer and lymphoma showed overexpression of all STEAP genes. It was also found that STEAP genes’ expression levels were already deregulated in benign lesions. Regarding the prognostic value, it was found that STEAP1 (prostate), STEAP2 (brain and central nervous system), STEAP3 (kidney, leukemia and testicular) and STEAP4 (bladder, cervical, gastric) overexpression correlate with lower patient survival rate. However, in prostate cancer, overexpression of the STEAP4 gene was correlated with a higher survival rate. Overall, this study first showed that the expression levels of STEAP genes are highly variable in human cancers, which may be related to different patients’ outcomes.
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26
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Jiang H, Dong Y, Yan D, Wu Y, Wang Y, Ren Y, Mao G, Liang G, Liu W, Zhou Y, Huang Z, Qi L. The expression of STEAP4 in peripheral blood predicts the outcome of septic patients. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1519. [PMID: 34790725 PMCID: PMC8576732 DOI: 10.21037/atm-21-2794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 10/22/2021] [Indexed: 11/30/2022]
Abstract
Background Sepsis is a systemic disease characterized by extensive inflammatory responses and impaired organ function, which are characteristics that make it easily missed and complex to treat. A large number of laboratory and clinical studies on the diagnosis and treatment of sepsis have been continuously carried out, confirming the importance of mitochondrial function during the development of sepsis. STEAP4 is an important metalloreductase in mitochondria, which is involved in the biogenesis and respiratory chain of mitochondria. The role of STEAP4 in inflammation remains controversial. Research in this field may contribute to the development of new diagnostic and treatment options for sepsis. Methods The expression of STEAP4 was measured in the peripheral blood of patients with severe sepsis and compared with healthy controls. Cell and mouse inflammatory models were established to detect the expression of STEAP4 and other inflammatory cytokines. Results (I) The expression of STEAP4 in the peripheral blood of patients with severe sepsis is higher than that of healthy volunteers (P<0.01), which is related to the SOFA score and transaminase. (II) STEAP4 has a certain predictive effect on the outcome of patients [area under curve (AUC) =0.696, P<0.05, 95% CI: 0.528 to 0.833]. (III) Inflammation led to increased expression of STEAP4 gene in RAW264.7 cells and mouse liver tissue. Conclusions The expression of STEAP4 is elevated in the early stage of sepsis and the degree of its elevation can be used to predict the clinical outcome of sepsis patients.
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Affiliation(s)
- Haiyan Jiang
- Department of Health Medicine, Affiliated Hospital of Nantong University, Nantong, China.,Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Yansong Dong
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Dajun Yan
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Yao Wu
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Yue Wang
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Yuting Ren
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Guomin Mao
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Guiwen Liang
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Wei Liu
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, China
| | - Yang Zhou
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, China
| | - Zhongwei Huang
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Lei Qi
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, China.,Rugao Branch (Rugao Bo'ai Hospital), Affiliated Hospital of Nantong University, Nantong, China
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Pustular psoriasis: Molecular pathways and effects of spesolimab in generalized pustular psoriasis. J Allergy Clin Immunol 2021; 149:1402-1412. [PMID: 34678325 DOI: 10.1016/j.jaci.2021.09.035] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 08/17/2021] [Accepted: 09/07/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND The IL-36 pathway plays a key role in the pathogenesis of generalized pustular psoriasis (GPP). In a proof-of-concept clinical trial, treatment with spesolimab, an anti-IL-36 receptor antibody, resulted in rapid skin and pustular clearance in patients presenting with GPP flares. OBJECTIVE We sought to compare the molecular profiles of lesional and nonlesional skin from patients with GPP or palmoplantar pustulosis (PPP) with skin from healthy volunteers, and to investigate the molecular changes after spesolimab treatment in the skin and blood of patients with GPP flares. METHODS Pre- and post-treatment skin and blood samples were collected from patients with GPP who participated in a single-arm, phase I study (n = 7). Skin biopsies from patients with PPP (n = 8) and healthy volunteers (n = 16) were obtained for comparison at baseline. Biomarkers were assessed by RNA-sequencing, histopathology, and immunohistochemistry. RESULTS In GPP and PPP lesions, 1287 transcripts were commonly upregulated or downregulated. Selected transcripts from the IL-36 signaling pathway were upregulated in untreated GPP and PPP lesions. In patients with GPP, IL-36 pathway-related signatures, TH1/TH17 and innate inflammation signaling, neutrophilic mediators, and keratinocyte-driven inflammation pathways were downregulated by spesolimab as early as week 1. Spesolimab also decreased related serum biomarkers and cell populations in the skin lesions from patients with GPP, including CD3+ T, CD11c+, and IL-36γ+ cells and lipocalin-2-expressing cells. CONCLUSIONS In patients with GPP, spesolimab showed rapid modulation of commonly dysregulated molecular pathways in GPP and PPP, which may be associated with improved clinical outcomes.
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Generalized Pustular Psoriasis: Divergence of Innate and Adaptive Immunity. Int J Mol Sci 2021; 22:ijms22169048. [PMID: 34445754 PMCID: PMC8396665 DOI: 10.3390/ijms22169048] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 08/08/2021] [Accepted: 08/11/2021] [Indexed: 12/28/2022] Open
Abstract
Generalized pustular psoriasis (GPP) is a severe, relapsing, immune-mediated disease characterized by the presence of multiple sterile pustules all over the body. The exact pathomechanisms behind GPP remain elusive, although increased interest in the genetic basis and immunological disturbances have provided some revealing insights into the underlying signaling pathways and their mutual interaction. The genetic background of GPP has been thoroughly investigated over the past few years. The conducted studies have identified genetic variants that predispose to pustular forms of psoriasis. The loss-of-function mutation of the interleukin 36 receptor antagonist gene, along with rare gain-of-function mutations in the gene that encodes the keratinocyte signaling molecule (CARD14), are examples of the uncovered abnormalities. Interleukin 36 (IL-36), along with neutrophils, is now considered a central cytokine in GPP pathogenesis, with IL-36 signaling providing a link between innate and adaptive immune responses. More recently, a new concept of inflammation, caused by a predominantly genetically determined abnormal activation of innate immune response and leading to inflammatory keratinization, has arisen. GPP is currently considered a representative of this novel group of skin conditions, called autoinflammatory keratinization diseases. As no therapeutic agents have been approved for GPP to date in the United States and Europe, the novel anti-IL-36R antibodies are particularly promising and may revolutionize management of the disease.
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Kobayashi K, Kamekura R, Kato J, Kamiya S, Kamiya T, Takano K, Ichimiya S, Uhara H. Cigarette Smoke Underlies the Pathogenesis of Palmoplantar Pustulosis via an IL-17A-Induced Production of IL-36γ in Tonsillar Epithelial Cells. J Invest Dermatol 2021; 141:1533-1541.e4. [PMID: 33188781 DOI: 10.1016/j.jid.2020.09.028] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/24/2020] [Accepted: 09/09/2020] [Indexed: 02/08/2023]
Abstract
Palmoplantar pustulosis (PPP) is characterized by sterile pustules on the palms and soles. A strong association between PPP and tobacco smoking has been reported, and it has been speculated that the IL-17A pathway may play an important role in PPP. Recent studies have suggested that IL-36 plays a pivotal role in the pathogenesis of psoriasis and its subtypes. The relationships among IL-36, smoking, and PPP have not been examined. Here, we investigated the relationships among the smoking index, severity of the clinical condition of PPP, and in vitro dynamics of IL-36 in human tonsillar epithelial cells under the condition of exposure to a cigarette smoke extract. The results demonstrated that the Palmoplantar Pustulosis Area and Severity Index was strongly and positively correlated with the smoking index in female patients. Immunohistochemical examinations showed that IL-36γ was highly expressed in tonsillar epithelial cells from patients with PPP but not in those from patients with recurrent tonsillitis without PPP. The in vitro study revealed that IL-17A synergistically induced a release of IL-36γ under cigarette smoke extract exposure. These results suggest that local production of IL-36γ by epithelial cells induced by cigarette smoke exposure plays an important role in the pathogenesis of PPP.
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Affiliation(s)
- Keiju Kobayashi
- Department of Dermatology, School of Medicine, Sapporo Medical University, Sapporo, Japan; Department of Human Immunology, Research Institute for Frontier Medicine, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Ryuta Kamekura
- Department of Human Immunology, Research Institute for Frontier Medicine, School of Medicine, Sapporo Medical University, Sapporo, Japan; Department of Otolaryngology, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Junji Kato
- Department of Dermatology, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Shiori Kamiya
- Department of Dermatology, School of Medicine, Sapporo Medical University, Sapporo, Japan; Department of Human Immunology, Research Institute for Frontier Medicine, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Takafumi Kamiya
- Department of Dermatology, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Kenichi Takano
- Department of Otolaryngology, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Shingo Ichimiya
- Department of Human Immunology, Research Institute for Frontier Medicine, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Hisashi Uhara
- Department of Dermatology, School of Medicine, Sapporo Medical University, Sapporo, Japan.
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30
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The Usefulness of STEAP Proteins in Prostate Cancer Clinical Practice. Prostate Cancer 2021. [DOI: 10.36255/exonpublications.prostatecancer.steap.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2023] Open
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Zhou J, Luo Q, Cheng Y, Wen X, Liu J. An update on genetic basis of generalized pustular psoriasis (Review). Int J Mol Med 2021; 47:118. [PMID: 33955502 PMCID: PMC8083806 DOI: 10.3892/ijmm.2021.4951] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 03/11/2021] [Indexed: 01/28/2023] Open
Abstract
Generalized pustular psoriasis (GPP) is a rare and severe auto-inflammatory skin disease that is characterized by recurrent, acute onset, and generalized pustular eruptions on erythematous, inflamed skin. GPP is traditionally classified as a variant of psoriasis vulgaris, even though recent clinical, histological and genetic evidence suggests that it is a heterogeneous disease and requires a separate diagnosis. In recent years, variants of IL36RN, CARD14, AP1S3 and MPO genes have been identified as causative or contributing to genetic defects in a proportion of patients affected by GPP. These disease-related genes are involved in common inflammatory pathways, in particular in the IL-1/IL-36-chemokines-neutrophil pathogenic axis. At present, no standard therapeutic guidelines have been established for GPP management, and there is a profound need for novel efficacious treatments of GPP. Among them, biological agents antagonizing the IL-36 pathway are promising therapeutics. The aim of the present review is to provide the most recent updates on the genetics, genotype-phenotype correlation and pathological basis of GPP, as well as on biologic treatments available for GPP and relative clinical courses.
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Affiliation(s)
- Jiahong Zhou
- Department of Laboratory Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Qing Luo
- Department of Laboratory Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Yang Cheng
- Department of Laboratory Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Xia Wen
- Department of Laboratory Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Jinbo Liu
- Department of Laboratory Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
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32
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SnapshotDx Quiz: May 2021. J Invest Dermatol 2021. [DOI: 10.1016/j.jid.2021.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Pihlstrøm N, Jin Y, Nenseth Z, Kuzu OF, Saatcioglu F. STAMP2 Expression Mediated by Cytokines Attenuates Their Growth-Limiting Effects in Prostate Cancer Cells. Cancers (Basel) 2021; 13:cancers13071579. [PMID: 33808059 PMCID: PMC8036285 DOI: 10.3390/cancers13071579] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 03/24/2021] [Accepted: 03/26/2021] [Indexed: 01/22/2023] Open
Abstract
Simple Summary Prostate cancer (PCa) is the most common non-skin cancer and one of the leading causes of cancer death in men. Despite significant developments in therapy options with improved survival, no curative treatment is currently available. We have previously identified six transmembrane protein of prostate 2 (STAMP2) as an important factor for PCa growth and survival. We now show that STAMP2 expression is regulated by inflammatory signaling, which has recently been implicated in PCa. Two proinflammatory cytokines, interleukin 6 and interleukin 1 beta, synergize with each other to induce STAMP2 expression. Interestingly, STAMP2 knockdown increased the sensitivity of PCa cells to cytokine treatment. Thus, STAMP2 that acts as a survival factor in PCa, is both independently and synergistically regulated by inflammatory signaling that may affect disease progression. Abstract Inflammatory events and dysregulated cytokine expression are implicated in prostate cancer (PCa), but the underlying molecular mechanisms are poorly understood at present. We have previously identified six transmembrane protein of the prostate 2 (STAMP2, also known as STEAP4) as an androgen-regulated gene, as well as a key regulator of PCa growth and survival. STAMP2 is also regulated by, and participates in, inflammatory signaling in other tissues and pathologies. Here, we show that the proinflammatory cytokines interleukin 6 (IL-6) and Interleukin 1 beta (IL-1β) significantly increase and strongly synergize in promoting STAMP2 expression in PCa cells. The two cytokines increase androgen-induced STAMP2 expression, but not expression of other known androgen target genes, suggesting a unique interplay of androgens and cytokines in regulating STAMP2 expression. Interestingly, STAMP2 knockdown significantly increased the ability of IL-6 and IL-1β to inhibit PCa cell growth in vitro. These results suggest that STAMP2 may represent a unique node through which inflammatory events mediate their effects on PCa growth and survival.
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Affiliation(s)
- Nicklas Pihlstrøm
- Department of Biosciences, University of Oslo, 0315 Oslo, Norway; (N.P.); (Y.J.); (Z.N.)
| | - Yang Jin
- Department of Biosciences, University of Oslo, 0315 Oslo, Norway; (N.P.); (Y.J.); (Z.N.)
| | - Zeynep Nenseth
- Department of Biosciences, University of Oslo, 0315 Oslo, Norway; (N.P.); (Y.J.); (Z.N.)
| | - Omer F. Kuzu
- Department of Biosciences, University of Oslo, 0315 Oslo, Norway; (N.P.); (Y.J.); (Z.N.)
- Correspondence: (O.F.K.); (F.S.); Tel.: +47-22-854-569 (F.S.); Fax: +47-22-857-207 (F.S.)
| | - Fahri Saatcioglu
- Department of Biosciences, University of Oslo, 0315 Oslo, Norway; (N.P.); (Y.J.); (Z.N.)
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, 0188 Oslo, Norway
- Correspondence: (O.F.K.); (F.S.); Tel.: +47-22-854-569 (F.S.); Fax: +47-22-857-207 (F.S.)
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Iznardo H, Puig L. The interleukin-1 family cytokines in psoriasis: pathogenetic role and therapeutic perspectives. Expert Rev Clin Immunol 2021; 17:187-199. [PMID: 33538202 DOI: 10.1080/1744666x.2021.1886081] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: IL-1 family cytokines play an important role in the innate immune system and their uncontrolled activation and expression can initiate a pathologic inflammatory response. Their role in psoriasis, pustular psoriasis, and psoriatic arthritis has been studied, and they offer potential interest as therapeutic targets.Areas covered: This review focuses on the role that interleukin (IL)-1 family cytokines play in psoriasis pathogenesis, with a special focus on pustular psoriasis, and how these cytokines can be used as therapeutic targets. Using PubMed, we review the literature for articles related to IL-1 family cytokines and psoriasis, focusing on pustular psoriasis, and including pathogenesis, genetics and therapeutic targets.Expert opinion: IL-1 and IL-36 cytokines act as critical drivers of the autoinflammatory responses involved in pustular psoriasis. Studies on the specific role of each IL-1 cytokine are needed, as well as of their regulatory pathways. Targeting of IL-1 family cytokines has been used in pustular psoriasis, with IL-1 and IL-36 R blockade showing promising results.
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Affiliation(s)
- Helena Iznardo
- Department of Dermatology, Hospital De La Santa Creu I Sant Pau, Barcelona, Spain.,Department of Medicine, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Lluís Puig
- Department of Dermatology, Hospital De La Santa Creu I Sant Pau, Barcelona, Spain.,Department of Medicine, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
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35
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Signatures of Dermal Fibroblasts from RDEB Pediatric Patients. Int J Mol Sci 2021; 22:ijms22041792. [PMID: 33670258 PMCID: PMC7918539 DOI: 10.3390/ijms22041792] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/05/2021] [Accepted: 02/08/2021] [Indexed: 12/13/2022] Open
Abstract
The recessive form of dystrophic epidermolysis bullosa (RDEB) is a debilitating disease caused by impairments in the junctions of the dermis and the basement membrane of the epidermis. Mutations in the COL7A1 gene induce multiple abnormalities, including chronic inflammation and profibrotic changes in the skin. However, the correlations between the specific mutations in COL7A1 and their phenotypic output remain largely unexplored. The mutations in the COL7A1 gene, described here, were found in the DEB register. Among them, two homozygous mutations and two cases of compound heterozygous mutations were identified. We created the panel of primary patient-specific RDEB fibroblast lines (FEB) and compared it with control fibroblasts from healthy donors (FHC). The set of morphological features and the contraction capacity of the cells distinguished FEB from FHC. We also report the relationships between the mutations and several phenotypic traits of the FEB. Based on the analysis of the available RNA-seq data of RDEB fibroblasts, we performed an RT-qPCR gene expression analysis of our cell lines, confirming the differential status of multiple genes while uncovering the new ones. We anticipate that our panels of cell lines will be useful not only for studying RDEB signatures but also for investigating the overall mechanisms involved in disease progression.
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36
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Uppala R, Tsoi LC, Harms PW, Wang B, Billi AC, Maverakis E, Michelle Kahlenberg J, Ward NL, Gudjonsson JE. "Autoinflammatory psoriasis"-genetics and biology of pustular psoriasis. Cell Mol Immunol 2020; 18:307-317. [PMID: 32814870 DOI: 10.1038/s41423-020-0519-3] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 07/20/2020] [Indexed: 02/08/2023] Open
Abstract
Psoriasis is a chronic inflammatory skin condition that has a fairly wide range of clinical presentations. Plaque psoriasis, which is the most common manifestation of psoriasis, is located on one end of the spectrum, dominated by adaptive immune responses, whereas the rarer pustular psoriasis lies on the opposite end, dominated by innate and autoinflammatory immune responses. In recent years, genetic studies have identified six genetic variants that predispose to pustular psoriasis, and these have highlighted the role of IL-36 cytokines as central to pustular psoriasis pathogenesis. In this review, we discuss the presentation and clinical subtypes of pustular psoriasis, contribution of genetic predisposing variants, critical role of the IL-36 family of cytokines in disease pathophysiology, and treatment perspectives for pustular psoriasis. We further outline the application of appropriate mouse models for the study of pustular psoriasis and address the outstanding questions and issues related to our understanding of the mechanisms involved in pustular psoriasis.
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Affiliation(s)
- Ranjitha Uppala
- Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA.,Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Lam C Tsoi
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Paul W Harms
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.,Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Bo Wang
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Allison C Billi
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Emanual Maverakis
- Department of Dermatology, University of California, Davis, Sacramento, CA, USA
| | - J Michelle Kahlenberg
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.,A. Alfred Taubman Medical Research Institute, Ann Arbor, MI, USA
| | - Nicole L Ward
- Departments of Nutrition and Dermatology, Case Western Reserve University, Cleveland, OH, USA
| | - Johann E Gudjonsson
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA. .,A. Alfred Taubman Medical Research Institute, Ann Arbor, MI, USA.
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Manils J, Webb LV, Howes A, Janzen J, Boeing S, Bowcock AM, Ley SC. CARD14 E138A signalling in keratinocytes induces TNF-dependent skin and systemic inflammation. eLife 2020; 9:e56720. [PMID: 32597759 PMCID: PMC7351492 DOI: 10.7554/elife.56720] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Accepted: 06/26/2020] [Indexed: 12/15/2022] Open
Abstract
To investigate how the CARD14E138A psoriasis-associated mutation induces skin inflammation, a knock-in mouse strain was generated that allows tamoxifen-induced expression of the homologous Card14E138A mutation from the endogenous mouse Card14 locus. Heterozygous expression of CARD14E138A rapidly induced skin acanthosis, immune cell infiltration and expression of psoriasis-associated pro-inflammatory genes. Homozygous expression of CARD14E138A induced more extensive skin inflammation and a severe systemic disease involving infiltration of myeloid cells in multiple organs, temperature reduction, weight loss and organ failure. This severe phenotype resembled acute exacerbations of generalised pustular psoriasis (GPP), a rare form of psoriasis that can be caused by CARD14 mutations in patients. CARD14E138A-induced skin inflammation and systemic disease were independent of adaptive immune cells, ameliorated by blocking TNF and induced by CARD14E138A signalling only in keratinocytes. These results suggest that anti-inflammatory therapies specifically targeting keratinocytes, rather than systemic biologicals, might be effective for GPP treatment early in disease progression.
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Affiliation(s)
- Joan Manils
- The Francis Crick InstituteLondonUnited Kingdom
- Department of Immunology & Inflammation, Imperial College LondonLondonUnited Kingdom
| | | | - Ashleigh Howes
- National Heart & Lung Institute, Imperial College LondonLondonUnited Kingdom
| | - Julia Janzen
- Department of Immunology & Inflammation, Imperial College LondonLondonUnited Kingdom
| | - Stefan Boeing
- The Francis Crick InstituteLondonUnited Kingdom
- Bioinformatics and Biostatistics, The Francis Crick InstituteLondonUnited Kingdom
- Crick Scientific Computing - Digital Development Team, The Francis Crick InstituteLondonUnited Kingdom
| | - Anne M Bowcock
- National Heart & Lung Institute, Imperial College LondonLondonUnited Kingdom
- Departments of Oncological Science, Dermatology, and Genetics & Genome Sciences, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Steven C Ley
- Department of Immunology & Inflammation, Imperial College LondonLondonUnited Kingdom
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38
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Review-Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis. Int J Mol Sci 2020; 21:ijms21030699. [PMID: 31973112 PMCID: PMC7037913 DOI: 10.3390/ijms21030699] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 01/14/2020] [Accepted: 01/16/2020] [Indexed: 12/14/2022] Open
Abstract
During the last decades, high-throughput assessment of gene expression in patient tissues using microarray technology or RNA-Seq took center stage in clinical research. Insights into the diversity and frequency of transcripts in healthy and diseased conditions provide valuable information on the cellular status in the respective tissues. Growing with the technique, the bioinformatic analysis toolkit reveals biologically relevant pathways which assist in understanding basic pathophysiological mechanisms. Conventional classification systems of inflammatory skin diseases rely on descriptive assessments by pathologists. In contrast to this, molecular profiling may uncover previously unknown disease classifying features. Thereby, treatments and prognostics of patients may be improved. Furthermore, disease models in basic research in comparison to the human disease can be directly validated. The aim of this article is not only to provide the reader with information on the opportunities of these techniques, but to outline potential pitfalls and technical limitations as well. Major published findings are briefly discussed to provide a broad overview on the current findings in transcriptomics in inflammatory skin diseases.
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39
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Abstract
Introduction: Generalized pustular psoriasis (GPP) is a rare, severe relapsing/remitting, multisystem disease that can be difficult to treat. Recent clinical, histological, and genetic evidence suggests that GPP is a distinct clinical entity from plaque psoriasis and requires a separate diagnosis. The interleukin-36 pathway appears to be central to GPP pathogenesis. As no therapeutic agents have been approved for GPP to date in the United States or Europe, the introduction of anti-IL-36 therapies may change disease management. Areas covered: Using PubMed and Google Scholar, we reviewed the literature for articles related to GPP, psoriasis, and the genetics, pathogenesis, and treatment thereof. Expert opinion: New therapeutic options and updated guidelines for GPP treatment are needed. Ideal agents would have rapid onset of action and rapid time to achieve disease clearance, have the ability to prevent acute flares and avert recurrence, and possess a favorable safety profile. Such therapies should be readily accessible via approval or listing on formularies. Scoring systems to establish GPP disease burden and objective outcome measures could also help with further evaluation of therapies and treatment access issues. IL-36 remains a promising target, as supported by early phase data suggesting efficacy and safety for a novel anti-IL-36 therapy.
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Affiliation(s)
- Melinda J Gooderham
- SKiN Centre for Dermatology, Probity Medical Research, Queen's University , Peterborough , ON , Canada
| | - Abby S Van Voorhees
- Department of Dermatology, Eastern Virginia Medical School , Norfolk , VA , USA
| | - Mark G Lebwohl
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai , New York , NY , USA
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40
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Haidari W, Feldman SR. Rates of psoriasis in patients with palmoplantar pustulosis. Br J Dermatol 2019; 181:887-888. [DOI: 10.1111/bjd.18314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Affiliation(s)
- W. Haidari
- Department of Dermatology (Center for Dermatology Research) Wake Forest School of Medicine, Medical Center Boulevard Winston‐Salem NC 27157‐1071 U.S.A
| | - S. R. Feldman
- Department of Dermatology (Center for Dermatology Research) Wake Forest School of Medicine, Medical Center Boulevard Winston‐Salem NC 27157‐1071 U.S.A
- Department of Pathology Wake Forest School of Medicine, Medical Center Boulevard Winston‐Salem NC 27157‐1071 U.S.A
- Department of Social Sciences & Health Policy Wake Forest School of Medicine, Medical Center Boulevard Winston‐Salem NC 27157‐1071 U.S.A
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41
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Furue K, Ito T, Tanaka Y, Yumine A, Hashimoto-Hachiya A, Takemura M, Murata M, Yamamura K, Tsuji G, Furue M. Cyto/chemokine profile of in vitro scratched keratinocyte model: Implications of significant upregulation of CCL20, CXCL8 and IL36G in Koebner phenomenon. J Dermatol Sci 2019; 94:244-251. [DOI: 10.1016/j.jdermsci.2019.04.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 04/09/2019] [Indexed: 02/06/2023]
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42
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Xiaoling Y, Chao W, Wenming W, Feng L, Hongzhong J. Interleukin (IL)-8 and IL-36γ but not IL-36Ra are related to acrosyringia in pustule formation associated with palmoplantar pustulosis. Clin Exp Dermatol 2018; 44:52-57. [PMID: 29896852 DOI: 10.1111/ced.13689] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2017] [Indexed: 01/06/2023]
Affiliation(s)
- Y. Xiaoling
- Department of Dermatology; Peking Union Medical College Hospital; Beijing China
| | - W. Chao
- Department of Dermatology; Peking Union Medical College Hospital; Beijing China
| | - W. Wenming
- Department of Dermatology; Peking Union Medical College Hospital; Beijing China
| | - L. Feng
- Department of Dermatology; Peking Union Medical College Hospital; Beijing China
| | - J. Hongzhong
- Department of Dermatology; Peking Union Medical College Hospital; Beijing China
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43
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Wang L, Yu X, Wu C, Zhu T, Wang W, Zheng X, Jin H. RNA sequencing-based longitudinal transcriptomic profiling gives novel insights into the disease mechanism of generalized pustular psoriasis. BMC Med Genomics 2018; 11:52. [PMID: 29871627 PMCID: PMC5989375 DOI: 10.1186/s12920-018-0369-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 05/24/2018] [Indexed: 12/13/2022] Open
Abstract
Background Generalized pustular psoriasis (GPP) is a rare, episodic, potentially life-threatening inflammatory disease. However, the pathogenesis of GPP, and universally accepted therapies for treating it, remain undefined. Methods To better understand the disease mechanism of GPP, we performed a transcriptome analysis to profile the gene expression of peripheral blood mononuclear cells (PBMCs) from patients enrolled at the time of diagnosis and receiving follow-up treatment for up to 6 months. Results RNA sequencing data revealed that gene expression in five GPP patients’ PBMCs was profoundly altered following acitretin treatment. Differentially expressed gene (DEG) analysis suggested that genes related to psoriatic inflammation, including CXCL1, CXCL8 (IL-8), S100A8, S100A9, S100A12 and LCN2, were significantly downregulated in patients in remission from GPP. Functional enrichment and annotation analysis unveiled a cluster of DEGs significantly associated with the function of leukocytes, particularly neutrophils. Pathway analysis suggested that a variety of pro-inflammatory pathways were inhibited in patients in remission. This analysis not only reaffirmed known signaling pathways in GPP pathogenesis, but also implicated novel factors and pathways, such as cell cycle regulation pathways. Furthermore, regulator network analysis provided bioinformatics-based support for upstream molecules as potential therapeutic targets such as oncostatin M. Conclusions This longitudinal analysis of blood transcriptomes provides the first evidence that dysregulated gene expression in peripheral blood may significantly contribute to psoriatic inflammation in GPP patients. Novel canonical pathways and biomarkers identified in the current research may provide insights to help understand GPP pathobiology and advance novel therapeutics. Electronic supplementary material The online version of this article (10.1186/s12920-018-0369-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lingyan Wang
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoling Yu
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chao Wu
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Teng Zhu
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenming Wang
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaofeng Zheng
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongzhong Jin
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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44
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Arakawa A, Vollmer S, Besgen P, Galinski A, Summer B, Kawakami Y, Wollenberg A, Dornmair K, Spannagl M, Ruzicka T, Thomas P, Prinz JC. Unopposed IL-36 Activity Promotes Clonal CD4 + T-Cell Responses with IL-17A Production in Generalized Pustular Psoriasis. J Invest Dermatol 2017; 138:1338-1347. [PMID: 29288651 DOI: 10.1016/j.jid.2017.12.024] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 11/24/2017] [Accepted: 12/07/2017] [Indexed: 12/31/2022]
Abstract
Generalized pustular psoriasis (GPP) is the most severe psoriasis variant. Mutations in the IL-36 antagonist IL36RN, in CARD14 or AP1S3 provide genetic evidence for autoinflammatory etiology but cannot explain its pathogenesis completely. Here we demonstrate that unopposed IL-36 signaling promotes antigen-driven and likely pathogenic T-helper type 17 (Th17) responses in GPP. We observed that CD4+ T cells in blood and skin lesions of GPP patients were characterized by intense hyperproliferation, production of the GPP key mediator, IL-17A, and highly restricted TCR repertoires with identical T-cell clones in blood and skin lesions, indicating antigen-driven T-cell expansions. The clonally expanded CD4+ T cells were major producers of IL-17A. IL-36 signaling substantially enhanced TCR-mediated proliferation of CD4+ T cells. Moreover, GPP patients showed preferences for HLA-DRB1∗14, HLA-DQB1∗05, and HLA-DQB1∗03. We conclude that in GPP unopposed IL-36 signaling and certain HLA-class II alleles may cooperate in promoting antigen-driven Th17 responses, which in the obvious absence of exogenous triggers may reflect autoimmune reactions. This study reveals a pathogenic pathway where innate immune dysregulation promotes T-cell-mediated inflammation in GPP.
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Affiliation(s)
- Akiko Arakawa
- Department of Dermatology and Allergology, University Hospital, Ludwig-Maximilian-University, Munich, Germany.
| | - Sigrid Vollmer
- Department of Dermatology and Allergology, University Hospital, Ludwig-Maximilian-University, Munich, Germany
| | - Petra Besgen
- Department of Dermatology and Allergology, University Hospital, Ludwig-Maximilian-University, Munich, Germany
| | - Adrian Galinski
- Department of Dermatology and Allergology, University Hospital, Ludwig-Maximilian-University, Munich, Germany
| | - Burkhard Summer
- Department of Dermatology and Allergology, University Hospital, Ludwig-Maximilian-University, Munich, Germany
| | - Yoshio Kawakami
- Department of Dermatology and Allergology, University Hospital, Ludwig-Maximilian-University, Munich, Germany
| | - Andreas Wollenberg
- Department of Dermatology and Allergology, University Hospital, Ludwig-Maximilian-University, Munich, Germany
| | - Klaus Dornmair
- Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilian-University, Munich, Germany
| | - Michael Spannagl
- Laboratory of Immunogenetics and Molecular Diagnostics, University Hospital, Ludwig-Maximilian-University, Munich, Germany
| | - Thomas Ruzicka
- Department of Dermatology and Allergology, University Hospital, Ludwig-Maximilian-University, Munich, Germany
| | - Peter Thomas
- Department of Dermatology and Allergology, University Hospital, Ludwig-Maximilian-University, Munich, Germany
| | - Jörg C Prinz
- Department of Dermatology and Allergology, University Hospital, Ludwig-Maximilian-University, Munich, Germany.
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