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Jiang L, Zhang S, Jiang C, Chen H, Huang J, Yang J, Chi H, Wu Q, Yang G. Integrative biomarker discovery and immune profiling for ulcerative colitis: a multi-methodological approach. Sci Rep 2024; 14:24290. [PMID: 39414957 PMCID: PMC11484944 DOI: 10.1038/s41598-024-75797-0] [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: 11/18/2023] [Accepted: 10/08/2024] [Indexed: 10/18/2024] Open
Abstract
Background We aimed to pinpoint biomarkers, create a diagnostic model for ulcerative colitis (UC), and delve into its immune features to better understand this autoimmune condition. Methods The sequencing data for both the UC and the control groups were obtained from GEO, including both bulk and single-cell data. Using GSE87466 as training group, we applied differential analysis, WGCNA, PPI, LASSO, RF, and SVM-RFE for biomarker selection. A neural network shaped our diagnostic model, corroborated by GSE92415 as the validation cohort with ROC assessment. Immune cell profiling was conducted using CIBERSORT. Results 53 disease-associated genes were screened. Enrichment analysis highlighted roles in complement cascades and cell adhesion. Eight biomarkers were finally identified through multiple machine learning and PPI: B4GALNT2, PDZK1IP1, FAM195A, REG4, MTMR11, FLJ35024, CD55, and CD44. The diagnostic model had AUCs of 0.984 (training group) and 0.957 (validation group). UC tissues revealed heightened plasma cells, CD8 T cells, and other immune cells. Two unique UC immune patterns emerged, with certain T and NK cells central to immune modulation. Conclusion We identified eight biomarkers of UC by various methods, constructed a diagnostic model through neural networks, and explored the immune complexity of the disease, which contributes to the diagnosis and treatment of UC.
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Affiliation(s)
- Lai Jiang
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, and University Hospital, Macau University of Science and Technology, Macau, Macao SAR, China
- Clinical Medical College, Southwest Medical University, Luzhou, 646000, China
- Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Guangdong-Macao ln-Depth Cooperation Zone in Hengqin, Zhuhai, 519000, China
| | - Shengke Zhang
- Clinical Medical College, Southwest Medical University, Luzhou, 646000, China
| | - Chenglu Jiang
- Clinical Medical College, Southwest Medical University, Luzhou, 646000, China
| | - Haiqing Chen
- Clinical Medical College, Southwest Medical University, Luzhou, 646000, China
| | - Jinbang Huang
- Clinical Medical College, Southwest Medical University, Luzhou, 646000, China
| | - Jinyan Yang
- Clinical Medical College, Southwest Medical University, Luzhou, 646000, China
| | - Hao Chi
- Clinical Medical College, Southwest Medical University, Luzhou, 646000, China.
| | - Qibiao Wu
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, and University Hospital, Macau University of Science and Technology, Macau, Macao SAR, China.
- Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Guangdong-Macao ln-Depth Cooperation Zone in Hengqin, Zhuhai, 519000, China.
| | - Guanhu Yang
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, and University Hospital, Macau University of Science and Technology, Macau, Macao SAR, China.
- Department of Specialty Medicine, Ohio University, Athens, OH, 45701, USA.
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Abdelaziz I, Bounaama A, Djerdjouri B, Amir-Tidadini ZC. Low-dose dimethylfumarate attenuates colitis-associated cancer in mice through M2 macrophage polarization and blocking oxidative stress. Toxicol Appl Pharmacol 2024; 489:117018. [PMID: 38945373 DOI: 10.1016/j.taap.2024.117018] [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: 02/01/2024] [Revised: 06/13/2024] [Accepted: 06/26/2024] [Indexed: 07/02/2024]
Abstract
Colitis-associated cancer (CAC) is an aggressive subtype of colorectal cancer that can develop in ulcerative colitis patients and is driven by chronic inflammation and oxidative stress. Current chemotherapy for CAC, based on 5-fluorouracil and oxalipltin, is not fully effective and displays severe side effects, prompting the search for alternative therapies. Dimethylfumarate (DMF), an activator of the nuclear factor erythroid 2-related factor 2 (NRF2), is a potent antioxidant and immunomodelatrory drug used in the treatment of multiple sclerosis and showed a strong anti-inflammatory effect on experimental colitis. Here, we investigated the chemotherapeutic effect of DMF on an experimental model of CAC. Male NMRI mice were given two subcutaneous injections of 1,2 Dimethylhydrazine (DMH), followed by three cycles of dextran sulfate sodium (DSS). Low-dose (DMF30) and high-dose of DMF (DMF100) or oxaliplatin (OXA) were administered from the 8th to 12th week of the experiment, and then the colon tissues were analysed histologically and biochemically. DMH/DSS induced dysplastic aberrant crypt foci (ACF), oxidative stress, and severe colonic inflammation, with a predominance of pro-inflammatory M1 macrophages. As OXA, DMF30 reduced ACF multiplicity and crypt dysplasia, but further restored redox status, and reduced colitis severity by shifting macrophages towards the anti-inflammatory M2 phenotype. Surprisingly, DMF100 exacerbated ACF multiplicity, oxidative stress, and colon inflammation, likely through NRF2 and p53 overexpression in colonic inflammatory cells. DMF had a dual effect on CAC. At low dose, DMF is chemotherapeutic and acts as an antioxidant and immunomodulator, whereas at high dose, DMF is pro-oxidant and exacerbates colitis-associated cancer.
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Affiliation(s)
- Ismahane Abdelaziz
- Tamayouz_Laboratory of Cellular and Molecular Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria
| | - Abdelkader Bounaama
- Tamayouz_Laboratory of Cellular and Molecular Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria.
| | - Bahia Djerdjouri
- Tamayouz_Laboratory of Cellular and Molecular Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria
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3
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Yip JLK, Balasuriya GK, Hill-Yardin EL, Spencer SJ. The gut-brain and gut-macrophage contribution to gastrointestinal dysfunction with systemic inflammation. Brain Behav Immun 2024; 119:867-877. [PMID: 38750700 DOI: 10.1016/j.bbi.2024.05.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 04/24/2024] [Accepted: 05/12/2024] [Indexed: 05/19/2024] Open
Abstract
The gastrointestinal tract is one of the main organs affected during systemic inflammation and disrupted gastrointestinal motility is a major clinical manifestation. Many studies have investigated the involvement of neuroimmune interactions in regulating colonic motility during localized colonic inflammation, i.e., colitis. However, little is known about how the enteric nervous system and intestinal macrophages contribute to dysregulated motility during systemic inflammation. Given that systemic inflammation commonly results from the innate immune response against bacterial infection, we mimicked bacterial infection by administering lipopolysaccharide (LPS) to rats and assessed colonic motility using ex vivo video imaging techniques. We utilized the Cx3cr1-Dtr rat model of transient depletion of macrophages to investigate the role of intestinal macrophages in regulating colonic motility during LPS infection. To investigate the role of inhibitory enteric neurotransmission on colonic motility following LPS, we applied the nitric oxide synthase inhibitor, Nω-nitro-L-arginine (NOLA). Our results confirmed an increase in colonic contraction frequency during LPS-induced systemic inflammation. However, neither the depletion of intestinal macrophages, nor the suppression of inhibitory enteric nervous system activity impacted colonic motility disruption during inflammation. This implies that the interplay between the enteric nervous system and intestinal macrophages is nuanced, and complex, and further investigation is needed to clarify their joint roles in colonic motility.
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Affiliation(s)
- Jackson L K Yip
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, VIC, Australia
| | - Gayathri K Balasuriya
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, VIC, Australia; Department of Physiology and Cell Biology, Kobe University School of Medicine, Kobe, Japan
| | - Elisa L Hill-Yardin
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, VIC, Australia
| | - Sarah J Spencer
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, VIC, Australia.
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4
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Liu W, Hu H, Li C, Li Y, Mao P, Fan B. Genetics of causal relationships between circulating inflammatory proteins and postherpetic neuralgia: a bidirectional Mendelian randomization study. Front Neurol 2024; 15:1405694. [PMID: 38974683 PMCID: PMC11225550 DOI: 10.3389/fneur.2024.1405694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Accepted: 06/05/2024] [Indexed: 07/09/2024] Open
Abstract
Objective According to data from several observational studies, there is a strong association between circulating inflammatory cytokines and postherpetic neuralgia (PHN), but it is not clear whether this association is causal or confounding; therefore, the main aim of the present study was to analyze whether circulating inflammatory proteins have a bidirectional relationship with PHN at the genetic inheritance level using a Mendelian randomization (MR) study. Methods The Genome-Wide Association Study (GWAS) database was used for our analysis. We gathered data on inflammation-related genetic variation from three GWASs of human cytokines. These proteins included 91 circulating inflammatory proteins, tumor necrosis factor-alpha (TNF-α), macrophage inflammatory protein 1b (MIP-1b), and CXC chemokine 13 (CXCL13). The PHN dataset was obtained from the FinnGen biobank analysis round 5, and consisted of 1,413 cases and 275,212 controls. We conducted a two-sample bidirectional MR study using the TwoSampleMR and MRPRESSO R packages (version R.4.3.1). Our main analytical method was inverse variance weighting (IVW), and we performed sensitivity analyses to assess heterogeneity and pleiotropy, as well as the potential influence of individual SNPs, to validate our findings. Results According to our forward analysis, five circulating inflammatory proteins were causally associated with the development of PHN: interleukin (IL)-18 was positively associated with PHN, and IL-13, fibroblast growth factor 19 (FGF-19), MIP-1b, and stem cell growth factor (SCF) showed reverse causality with PHN. Conversely, we found that PHN was closely associated with 12 inflammatory cytokines, but no significant correlation was found among the other inflammatory factors. Among them, only IL-18 had a bidirectional causal relationship with PHN. Conclusion Our research advances the current understanding of the role of certain inflammatory biomarker pathways in the development of PHN. Additional verification is required to evaluate the viability of these proteins as targeted inflammatory factors for PHN-based treatments.
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Affiliation(s)
- WenHui Liu
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - HuiMin Hu
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Chen Li
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - YiFan Li
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Peng Mao
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - BiFa Fan
- Department of Pain Management, China-Japan Friendship Hospital, Beijing, China
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5
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Jadhav A, Jagtap S, Vyavahare S, Sharbidre A, Kunchiraman B. Reviewing the potential of probiotics, prebiotics and synbiotics: advancements in treatment of ulcerative colitis. Front Cell Infect Microbiol 2023; 13:1268041. [PMID: 38145046 PMCID: PMC10739422 DOI: 10.3389/fcimb.2023.1268041] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 11/22/2023] [Indexed: 12/26/2023] Open
Abstract
Inflammatory bowel diseases (IBD) like Crohn's and ulcerative colitis (UC) are multifactorial pathologies caused by environmental factors and genetic background. UC is a chronic inflammatory disorder that specifically targets the colon, resulting in inflammation. Various chemical interventions, including aminosalicylates, corticosteroids, immunomodulators, and biological therapies, have been extensively employed for the purpose of managing symptoms associated with UC. Nevertheless, it is important to note that these therapeutic interventions may give rise to undesirable consequences, including, but not limited to, the potential for weight gain, fluid retention, and heightened vulnerability to infections. Emerging therapeutic approaches for UC are costly due to their chronic nature. Alternatives like synbiotic therapy, combining prebiotics and probiotics, have gained attention for mitigating dysbiosis in UC patients. Prebiotics promote beneficial bacteria proliferation, while probiotics establish a balanced gut microbiota and regulate immune system functionality. The utilisation of synbiotics has been shown to improve the inflammatory response and promote the resolution of symptoms in individuals with UC through the stimulation of beneficial bacteria growth and the enhancement of intestinal barrier integrity. Hence, this review article aims to explore the potential benefits and underlying reasons for incorporating alternative approaches in the management of UC with studies performed using prebiotics, probiotics, and synbiotics to treat ulcerative colitis and to highlight safety and considerations in UC and future perspectives. This will facilitate the utilisation of novel treatment strategies for the safer and more efficacious management of patients with UC.
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Affiliation(s)
- Apurva Jadhav
- Herbal Medicine, Interactive Research School for Health Affairs, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra, India
| | - Suresh Jagtap
- Herbal Medicine, Interactive Research School for Health Affairs, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra, India
| | - Suresh Vyavahare
- Sai Ayurved Medical College, Maharashtra University of Health Sciences, Solapur, Maharashtra, India
| | - Archana Sharbidre
- Department of Zoology, Savitribai Phule Pune University, Pune, Maharashtra, India
| | - Bipinraj Kunchiraman
- Microbial Biotechnology, Rajiv Gandhi Institute of IT & Biotechnology, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra, India
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6
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Wei L, Chen Z, Lv Q. Mucosal-associated invariant T cells display both pathogenic and protective roles in patients with inflammatory bowel diseases. Amino Acids 2023; 55:1819-1827. [PMID: 37819474 DOI: 10.1007/s00726-023-03344-8] [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: 08/21/2023] [Accepted: 09/26/2023] [Indexed: 10/13/2023]
Abstract
An important subtype of the innate-like T lymphocytes is mucosal-associated invariant T (MAIT) cells expressing a semi-invariant T cell receptor α (TCR-α) chain. MAIT cells could be activated mainly by TCR engagement or cytokines. They have been found to have essential roles in various immune mediated. There have been growing preclinical and clinical findings that show an association between MAIT cells and the physiopathology of inflammatory bowel diseases (IBD). Of note, published reports demonstrate contradictory findings regarding the role of MAIT cells in IBD patients. A number of reports suggests a protective effect, whereas others show a pathogenic impact. The present review article aimed to explore and discuss the findings of experimental and clinical investigations evaluating the effects of MAIT cells in IBD subjects and animal models. Findings indicate that MAIT cells could exert opposite effects in the course of IBD, including an anti-inflammatory protective effect of blood circulating MAIT cells and an effector pathogenic effect of colonic MAIT cells. Another important finding is that blood levels of MAIT cells can be considered as a potential biomarker in IBD patients.
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Affiliation(s)
- Lei Wei
- Department of General Surgery, Pudong New District Gongli Hospital of Shanghai, Shanghai, 200120, China
| | - Zhigang Chen
- Department of General Surgery, Pudong New District Gongli Hospital of Shanghai, Shanghai, 200120, China
| | - Qiang Lv
- Department of General Surgery, Pudong New District Gongli Hospital of Shanghai, Shanghai, 200120, China.
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7
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Mannon PJ. Immunologic Diseases of the Gastrointestinal Tract. Clin Immunol 2023. [DOI: 10.1016/b978-0-7020-8165-1.00075-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2023]
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8
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Vetrano S, Bouma G, Benschop RJ, Birngruber T, Costanzo A, D’Haens GRAM, Frasca L, Hillenbrand R, Iversen L, Johansen C, Kaser A, Koenen HJPM, Noehammer C, Peyrin-Biroulet L, Raes J, Ricotti L, Rosenstiel P, Satagopam VP, Schreiber S, Vermeire S, Wollenberg A, Weidinger S, Ziemek D, Danese S. ImmUniverse Consortium: Multi-omics integrative approach in personalized medicine for immune-mediated inflammatory diseases. Front Immunol 2022; 13:1002629. [PMID: 36439150 PMCID: PMC9682955 DOI: 10.3389/fimmu.2022.1002629] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 09/26/2022] [Indexed: 09/22/2023] Open
Abstract
Immune mediated inflammatory diseases (IMIDs) are a heterogeneous group of debilitating, multifactorial and unrelated conditions featured by a dysregulated immune response leading to destructive chronic inflammation. The immune dysregulation can affect various organ systems: gut (e.g., inflammatory bowel disease), joints (e.g., rheumatoid arthritis), skin (e.g., psoriasis, atopic dermatitis), resulting in significant morbidity, reduced quality of life, increased risk for comorbidities, and premature death. As there are no reliable disease progression and therapy response biomarkers currently available, it is very hard to predict how the disease will develop and which treatments will be effective in a given patient. In addition, a considerable proportion of patients do not respond sufficiently to the treatment. ImmUniverse is a large collaborative consortium of 27 partners funded by the Innovative Medicine Initiative (IMI), which is sponsored by the European Union (Horizon 2020) and in-kind contributions of participating pharmaceutical companies within the European Federation of Pharmaceutical Industries and Associations (EFPIA). ImmUniverse aims to advance our understanding of the molecular mechanisms underlying two immune-mediated diseases, ulcerative colitis (UC) and atopic dermatitis (AD), by pursuing an integrative multi-omics approach. As a consequence of the heterogeneity among IMIDs patients, a comprehensive, evidence-based identification of novel biomarkers is necessary to enable appropriate patient stratification that would account for the inter-individual differences in disease severity, drug efficacy, side effects or prognosis. This would guide clinicians in the management of patients and represent a major step towards personalized medicine. ImmUniverse will combine the existing and novel advanced technologies, including multi-omics, to characterize both the tissue microenvironment and blood. This comprehensive, systems biology-oriented approach will allow for identification and validation of tissue and circulating biomarker signatures as well as mechanistic principles, which will provide information about disease severity and future disease progression. This truly makes the ImmUniverse Consortium an unparalleled approach.
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Affiliation(s)
- Stefania Vetrano
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- IBD Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Gerben Bouma
- Clinical Pharmacology and Experimental Medicine, GlaxoSmithKline R&D, United Kingdom
| | - Robert J. Benschop
- Immunology and Translation, Eli Lilly and Company, Indianapolis, IN, United States
| | - Thomas Birngruber
- Joanneum Research GmbH, HEALTH - Institute for Biomedicine and Health Sciences, Graz, Austria
| | - Antonio Costanzo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Dermatology Unit, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - G. R. A. M. D’Haens
- Department of Gastroenterology and Hepatology, Academisch Medisch Centrum Bij De Universiteit Van Amsterdam, Amsterdam, Netherlands
| | - Loredana Frasca
- Pharmacological Research and Experimental Therapy Unit, Istituto Superiore Di Sanità, Roma, Italy
| | | | - Lars Iversen
- Department of Dermatology, Aarhus Universitetshospital, Aarhus, Denmark
| | | | - Arthur Kaser
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Hans J. P. M. Koenen
- Department of Laboratory Medicine, Laboratory of Medical Immunology, Stichting Radboud Universitair Medisch Centrum, Nijmegen, Netherlands
| | - Christa Noehammer
- Department of Health and Environment, AIT Austrian Institute of Technology GmbH, Vienna, Austria
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Centre Hospitalier Regional Universitaire Nancy, Nancy, France
| | - Jeroen Raes
- Department of Microbiology and Immunology, Vib Vzw, Gent, Belgium
| | - Leonardo Ricotti
- The BioRobotics Institute, Scuola Superiore Sant’Anna, Pisa, Italy
- Department of Excellence in Robotics & AI, Scuola Superiore Sant’Anna, Pisa, Italy
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital, Kiel, Germany
| | - Venkata P. Satagopam
- Luxembourg Centre for Systems Biomedicine, House of Biomedicine II, University of Luxembourg, Belvaux, Luxembourg
| | - Stefan Schreiber
- Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel University, Kiel, Germany
| | - Severine Vermeire
- Department of Gastroenterology and Hepatology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Andreas Wollenberg
- Department of Dermatology, Ludwig-Maximilian-University Munich, Munich, Germany
- Department of Dermatology, Free University Brussels, University Hospital Brussels, Brussels, Belgium
| | - Stephan Weidinger
- Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Daniel Ziemek
- Worldwide Research and Development, Pfizer Pharma, Berlin, Germany
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Department of Gastroenterology and Endoscopy IRCCS Ospedale San Raffaele, Milan, Italy
- University Vita-Salute San Raffaele, Milan, Italy
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Inflammatory Bowel Disease: A Review of Pre-Clinical Murine Models of Human Disease. Int J Mol Sci 2022; 23:ijms23169344. [PMID: 36012618 PMCID: PMC9409205 DOI: 10.3390/ijms23169344] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/15/2022] [Accepted: 08/17/2022] [Indexed: 12/11/2022] Open
Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) are both highly inflammatory diseases of the gastrointestinal tract, collectively known as inflammatory bowel disease (IBD). Although the cause of IBD is still unclear, several experimental IBD murine models have enabled researchers to make great inroads into understanding human IBD pathology. Here, we discuss the current pre-clinical experimental murine models for human IBD, including the chemical-induced trinitrobenzene sulfonic acid (TNBS) model, oxazolone and dextran sulphate sodium (DSS) models, the gene-deficient I-kappa-B kinase gamma (Iκκ-γ) and interleukin(IL)-10 models, and the CD4+ T-cell transfer model. We offer a comprehensive review of how these models have been used to dissect the etiopathogenesis of disease, alongside their limitations. Furthermore, the way in which this knowledge has led to the translation of experimental findings into novel clinical therapeutics is also discussed.
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Therapeutic effect of the sulforaphane derivative JY4 on ulcerative colitis through the NF-κB-p65 pathway. Inflammopharmacology 2022; 30:1717-1728. [PMID: 35943671 DOI: 10.1007/s10787-022-01044-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 06/22/2022] [Indexed: 11/05/2022]
Abstract
The efficacy of the sulforaphane derivative JY4 was evaluated in acute and chronic mouse models of ulcerative colitis induced by dextran sodium sulfate. Oral administration of JY4 led to significant improvements in symptoms, with recovery of body weight and colorectal length, together with reduced diarrhoea, bloody stools, ulceration of colonic tissue and infiltration of inflammatory cells. The oral bioavailability of JY4, determined by comparing oral dosing with injection into the tail vein, was 5.67%, which was comply with the idea in the intestinal function. Using a dual-luciferase reporter assay, immunofluorescence studies, western blot analysis and immunohistochemical staining, JY4 was shown to significant interfere with the NF-κB-p65 signaling pathway. By preventing the activation of NF-κB-p65, JY4 inhibited the overexpression of downstream inflammatory factors, thereby exerting an anti-inflammatory effect on the intestinal tract. This study thus provides a promising candidate drug, and a new concept for the treatment of ulcerative colitis.
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11
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Ojo BA, VanDussen KL, Rosen MJ. The Promise of Patient-Derived Colon Organoids to Model Ulcerative Colitis. Inflamm Bowel Dis 2022; 28:299-308. [PMID: 34251431 PMCID: PMC8804507 DOI: 10.1093/ibd/izab161] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Indexed: 12/11/2022]
Abstract
Physiologic, molecular, and genetic findings all point to impaired intestinal epithelial function as a key element in the multifactorial pathogenesis of ulcerative colitis (UC). The lack of epithelial-directed therapies is a conspicuous weakness of our UC therapeutic armamentarium. However, a critical barrier to new drug discovery is the lack of preclinical human models of UC. Patient tissue-derived colon epithelial organoids (colonoids) are primary epithelial stem cell-derived in vitro structures capable of self-organization and self-renewal that hold great promise as a human preclinical model for UC drug development. Several single and multi-tissue systems for colonoid culture have been developed, including 3-dimensional colonoids grown in a gelatinous extracellular matrix, 2-dimensional polarized monolayers, and colonoids on a chip that model luminal and blood flow and nutrient delivery. A small number of pioneering studies suggest that colonoids derived from UC patients retain some disease-related transcriptional and epigenetic changes, but they also raise questions regarding the persistence of inflammatory transcriptional programs in culture over time. Additional research is needed to fully characterize the extent to which and under what conditions colonoids accurately model disease-associated epithelial molecular and functional aberrations. With further advancement and standardization of colonoid culture methodology, colonoids will likely become an important tool for realizing precision medicine in UC.
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Affiliation(s)
- Babajide A Ojo
- Divisions of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
| | - Kelli L VanDussen
- Divisions of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
- Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
| | - Michael J Rosen
- Divisions of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
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12
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Xue NN, He M, Li Y, Wu JZ, Du WW, Wu XM, Yang ZZ, Zhang CG, Li QY, Xiao H. Periplaneta americana extract promotes intestinal mucosa repair of ulcerative colitis in rat. Acta Cir Bras 2020; 35:e202001002. [PMID: 33237174 PMCID: PMC7709898 DOI: 10.1590/s0102-865020200100000002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 09/04/2020] [Indexed: 12/12/2022] Open
Abstract
PURPOSE To investigate the mechanism of Periplaneta americana extract promoting intestinal mucosal repair of OXZ-induced colitis in rat. METHODS All experiments used an equal number of male and female SD rats (n=48). We injected OXZ into the colon to induce UC rat model. To determine the optimal concentration of P. Americana's extract (PA-40), it was classified into low (L), medium (M), and high (H) doses. After OXZ treatment, each drug was administered by enema for 7 consecutive days. Rats were divided into the following 6 groups: (1) Saline treatment group (NC), (2) OXZ treatment UC model group (MC), (3) OXZ + budesonide group (BUN), (4) OXZ + PA-40 L group, (5) OXZ + PA-40 M group, (6) OXZ + PA-40 H group. Disease activity index (DAI) scores, colon length, histopathological score, serum cytokine level (IL-4, IL-10, iNOS, tNOS), and amount of MPO, EGF, IL-13 in colonic mucosa were measured. RESULTS PA treatment had a significant healing effect on the OXZ-colitis model and significantly reduced the lesioned area, especially in the PA-40H groups. PA treatment did not alter the expression of IL-10 and MPO level, but increased EGF (epidermal growth factor) and decrease IL-13 in the colonic tissue. PA inhibited the rise of NOSs (nitric oxide synthase) and decreased the serum IL-4 level. CONCLUSIONS The data suggest that Periplaneta americana extract may be a potential compound for the treatment of colonic lesions. The mechanism may be related to inhibiting the secretion of IL-13 and promoting the formation of EGF.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Qi-yan Li
- The First People's Hospital of Yunnan Province, China
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13
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Longo S, Chieppa M, Cossa LG, Spinelli CC, Greco M, Maffia M, Giudetti AM. New Insights into Inflammatory Bowel Diseases from Proteomic and Lipidomic Studies. Proteomes 2020; 8:proteomes8030018. [PMID: 32784952 PMCID: PMC7565982 DOI: 10.3390/proteomes8030018] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 08/04/2020] [Accepted: 08/07/2020] [Indexed: 12/19/2022] Open
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) represent the two main forms of chronic inflammatory bowel diseases (IBD). The exact IBD etiology is not yet revealed but CD and UC are likely induced by an excessive immune response against normal constituents of the intestinal microbial flora. IBD diagnosis is based on clinical symptoms often combined with invasive and costly procedures. Thus, the need for more non-invasive markers is urgent. Several routine laboratory investigations have been explored as indicators of intestinal inflammation in IBD, including blood testing for C-reactive protein, erythrocyte sedimentation rate, and specific antibodies, in addition to stool testing for calprotectin and lactoferrin. However, none has been universally adopted, some have been well-characterized, and others hold great promise. In recent years, the technological developments within the field of mass spectrometry (MS) and bioinformatics have greatly enhanced the ability to retrieve, characterize, and analyze large amounts of data. High-throughput research allowed enhancing the understanding of the biology of IBD permitting a more accurate biomarker discovery than ever before. In this review, we summarize currently used IBD serological and stool biomarkers and how proteomics and lipidomics are contributing to the identification of IBD biomarkers.
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Affiliation(s)
- Serena Longo
- Department of Biological and Environmental Sciences and Technologies, University of Salento, via Monteroni 165, 73100 Lecce, Italy; (S.L.); (L.G.C.); (C.C.S.)
| | - Marcello Chieppa
- National Institute of Gastroenterology “S. de Bellis”, Institute of Research, Via Turi, 27, 70013 Castellana Grotte, Italy;
| | - Luca G. Cossa
- Department of Biological and Environmental Sciences and Technologies, University of Salento, via Monteroni 165, 73100 Lecce, Italy; (S.L.); (L.G.C.); (C.C.S.)
| | - Chiara C. Spinelli
- Department of Biological and Environmental Sciences and Technologies, University of Salento, via Monteroni 165, 73100 Lecce, Italy; (S.L.); (L.G.C.); (C.C.S.)
| | - Marco Greco
- Department of Mathematics and Physics “Ennio De Giorgi”, University of Salento, via Monteroni, 73100 Lecce, Italy;
| | - Michele Maffia
- Department of Biological and Environmental Sciences and Technologies, University of Salento, via Monteroni 165, 73100 Lecce, Italy; (S.L.); (L.G.C.); (C.C.S.)
- Correspondence: (M.M.); (A.M.G.)
| | - Anna M. Giudetti
- Department of Biological and Environmental Sciences and Technologies, University of Salento, via Monteroni 165, 73100 Lecce, Italy; (S.L.); (L.G.C.); (C.C.S.)
- Correspondence: (M.M.); (A.M.G.)
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Shi Y, Liu Z, Cui X, Zhao Q, Liu T. Intestinal vitamin D receptor knockout protects from oxazolone-induced colitis. Cell Death Dis 2020; 11:461. [PMID: 32541827 PMCID: PMC7296018 DOI: 10.1038/s41419-020-2653-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 05/05/2020] [Accepted: 05/06/2020] [Indexed: 11/25/2022]
Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) actually had different pathological mechanisms, as the former was mainly induced by Th1 and Th17 response and the latter by Th2 response. Our previous study found that oxazolone-induced Th2-mediated colitis could not be attenuated by vitamin D supplementation. This study investigated the influence of intestinal vitamin D receptor (VDR) knockout on oxazolone-induced colitis and explored the possible immunological mechanism. Intestinal VDR knockout mice had milder oxazolone-induced colitis than wildtype controls, as demonstrated by less body weight decrease and faster recovery, more intact local structure, reduced cell apoptosis, and better preserved barrier function. Th2-mediated inflammation was significantly inhibited by VDR deficiency. Meanwhile, the percentage of invariant natural killer T (iNKT) cells did not increase as much in intestinal VDR knockout mice as in wild-type controls, nor did the iNKT cells develop normally as in the controls. Intestinal VDR knockout protected against oxazolone-induced colitis in mice by blocking Th2 cell response and reducing the function of intestinal iNKT cells. Vitamin D status had no influence on the severity of colitis. This study may explain the diverse outcomes after vitamin D supplementation in literature and add some clue to the targeted therapy of IBD.
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Affiliation(s)
- Yongyan Shi
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.,Department of Medicine, Division of Biological Sciences, University of Chicago, Chicago, USA
| | - Ziyun Liu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xuewei Cui
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qun Zhao
- Department of Pediatric Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Tianjing Liu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China. .,Department of Medicine, Division of Biological Sciences, University of Chicago, Chicago, USA. .,Department of Pediatric Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China.
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15
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Kierkus J, Pesegova M, Klopocka M, Brankovic M, Kasai N, Efuni S, Kong J, Nakajima Y, Jordan C, Matsui T, Feagan BG, Strout V. Randomized, Ascending Dose, Phase 2 Study of KHK4083, an Anti-OX40 Monoclonal Antibody, in Moderately Active Ulcerative Colitis. CROHN'S & COLITIS 360 2020; 2:otaa049. [PMID: 36776497 PMCID: PMC9808818 DOI: 10.1093/crocol/otaa049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Indexed: 01/24/2023] Open
Abstract
Background OX40 (CD134) plays a role in the maintenance of late T-cell proliferation and survival. KHK4083 is a monoclonal antibody directed against OX40. We aimed to assess the safety and preliminary efficacy of KHK4083 in patients with moderately active ulcerative colitis (UC). Methods In this multicenter, double-blind, parallel-group, phase 2 study, patients with moderately active UC patients were randomized to ascending doses of intravenous KHK4083 (1, 3, or 10 mg/kg) or placebo every 2 weeks for 12 weeks. The primary endpoint was safety. The primary efficacy end point was the change from baseline in mean modified Mayo endoscopy subscore at week 12. Treatment with KHK4083 or placebo was continued every 4 weeks for up to 52 weeks in responders. Results Long-term treatment with KHK4083 was well tolerated, with treatment-related adverse events being predominantly transient mild-to-moderate infusion-related reactions. Exploratory analysis of biopsy samples showed the virtually complete elimination of OX40+ cells in colon mucosa after 12 weeks of KHK4083 treatment. There were no significant differences between any of the randomized KHK4083 dose groups and placebo for the mean change in Mayo endoscopy subscore from baseline to week 12. Conclusions KHK4083 can be safely administered intravenously at doses up to 10 mg/kg every 2 or 4 weeks for up to 52 weeks. Proof of pharmacodynamic action was confirmed by depletion of the elevated levels of the OX40+ cells associated with UC at all tested doses. Clinical response and mucosal healing (endoscopic improvement) in this population was not correlated with ablation of OX40+ T cells.
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Affiliation(s)
- Jaroslaw Kierkus
- Maternal, Pediatric and Adolescent Healthcare Centre, Gastroenterology Diagnostic Facility for Adults, Warsaw, Poland
| | - Marina Pesegova
- Department of Gastroenterology, Territorial Clinical Hospital, Krasnoyarsk, Russia
| | - Maria Klopocka
- Department of Gastroenterology and Nutrition, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Poland
| | - Marija Brankovic
- Gastroenterology Clinic, Bezanijska Kosa Clinical Hospital Centre, Belgrade, Serbia
| | - Noriyuki Kasai
- Kyowa Kirin Pharmaceutical Development, Inc., Princeton, New Jersey
| | - Sergey Efuni
- Kyowa Kirin Pharmaceutical Development, Inc., Princeton, New Jersey
| | - Jennifer Kong
- Robarts Clinical Trials, Western University, London, Ontario, Canada
| | - Yu Nakajima
- Kyowa Kirin Pharmaceutical Development, Inc., Princeton, New Jersey
| | - Christina Jordan
- Kyowa Kirin Pharmaceutical Development, Inc., Princeton, New Jersey
| | - Takeshi Matsui
- Kyowa Kirin Pharmaceutical Development, Inc., Princeton, New Jersey
| | - Brian G Feagan
- Robarts Clinical Trials, Western University, London, Ontario, Canada
| | - Vincent Strout
- Kyowa Kirin Pharmaceutical Development, Inc., Princeton, New Jersey,Address correspondence to: Vincent Strout, MBA, Kyowa Kirin Pharmaceutical Development, Inc., 212 Carnegie Center, Suite 400, Princeton, NJ 08540 ()
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Papoutsopoulou S, Satsangi J, Campbell BJ, Probert CS. Review article: impact of cigarette smoking on intestinal inflammation-direct and indirect mechanisms. Aliment Pharmacol Ther 2020; 51:1268-1285. [PMID: 32372449 DOI: 10.1111/apt.15774] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 04/13/2020] [Accepted: 04/16/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND The inflammatory bowel diseases, Crohn's disease and ulcerative colitis are related multifactorial diseases. Their pathogenesis is influenced by each individual's immune system, the environmental factors within exposome and genetic predisposition. Smoking habit is the single best-established environmental factor that influences disease phenotype, behaviour and response to therapy. AIM To assess current epidemiological, experimental and clinical evidence that may explain how smoking impacts on the pathogenesis of inflammatory bowel disease. METHODS A Medline search for 'cigarette smoking', in combination with terms including 'passive', 'second-hand', 'intestinal inflammation', 'Crohn's disease', 'ulcerative colitis', 'colitis'; 'intestinal epithelium', 'immune system', 'intestinal microbiota', 'tight junctions', 'mucus', 'goblet cells', 'Paneth cells', 'autophagy'; 'epigenetics', 'genes', 'DNA methylation', 'histones', 'short noncoding/long noncoding RNAs'; 'carbon monoxide/CO' and 'nitric oxide/NO' was performed. RESULTS Studies found evidence of direct and indirect effects of smoking on various parameters, including oxidative damage, impairment of intestinal barrier and immune cell function, epigenetic and microbiota composition changes, that contribute to the pathogenesis of inflammatory bowel disease. CONCLUSIONS Cigarette smoking promotes intestinal inflammation by affecting the function and interactions among intestinal epithelium, immune system and microbiota/microbiome.
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Affiliation(s)
- Stamatia Papoutsopoulou
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Jack Satsangi
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Barry J Campbell
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Chris S Probert
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
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Hoving JC, Keeton R, Höft MA, Ozturk M, Otieno-Odhiambo P, Brombacher F. IL-4 Receptor-Alpha Signalling of Intestinal Epithelial Cells, Smooth Muscle Cells, and Macrophages Plays a Redundant Role in Oxazolone Colitis. Mediators Inflamm 2020; 2020:4361043. [PMID: 32410852 PMCID: PMC7201672 DOI: 10.1155/2020/4361043] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 12/05/2019] [Accepted: 12/10/2019] [Indexed: 11/29/2022] Open
Abstract
A hallmark of ulcerative colitis is the chronic colonic inflammation, which is the result of a dysregulated intestinal mucosal immune response. Epithelial barrier disruption which allows the entry of microorganisms eventually leads to more aggressive inflammation and potentially the removal of the colon. We have previously shown that the T helper- (Th-) type 2 cytokines, Interleukin- (IL-) 4 and IL-13, mediate CD4+ T cell- or B cell-driven inflammation in the oxazolone-induced mouse model of ulcerative colitis. In contrast, mice deficient in the shared receptor of IL-4 and IL-13, IL-4 receptor-alpha (IL-4Rα), on all cells develop an exacerbated disease phenotype. This suggests that a regulatory role of IL-4Rα is required to protect against severe colitis. However, the cell populations responsible for regulating the severity of disease onset through IL-4Rα in colitis are yet to be identified. By deleting IL-4Rα on specific cell subsets shown to play a role in mediating colitis, we determined their role in a loss of function approach. Our data demonstrated that the loss of IL-4Rα signalling on intestinal epithelial cells, smooth muscle cells, and macrophages/neutrophils had no effect on alleviating the pathology associated with colitis. These results suggest that IL-4/IL-13 signalling through IL-4Rα on nonhematopoietic intestinal epithelial or smooth muscle cells and hematopoietic macrophage/neutrophils has a redundant role in driving acute oxazolone colitis.
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Affiliation(s)
- Jennifer Claire Hoving
- AFGrica Medical Mycology Research Unit, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, South Africa, MRC Centre for Medical Mycology at the University of Exeter, Geoffrey Pope Building Stocker Road, Exeter, UK
- Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa
| | - Roanne Keeton
- Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa
| | - Maxine A. Höft
- AFGrica Medical Mycology Research Unit, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, South Africa, MRC Centre for Medical Mycology at the University of Exeter, Geoffrey Pope Building Stocker Road, Exeter, UK
- Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa
| | - Mumin Ozturk
- Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
| | - Patricia Otieno-Odhiambo
- AFGrica Medical Mycology Research Unit, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, South Africa, MRC Centre for Medical Mycology at the University of Exeter, Geoffrey Pope Building Stocker Road, Exeter, UK
- Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa
| | - Frank Brombacher
- Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
- South African Medical Research Council (SAMRC), South Africa
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Maruszewska-Cheruiyot M, Donskow-Łysoniewska K, Doligalska M. Helminth therapy – local and systemic activity, on example of inflammatory bowel diseases and multiple sclerosis. POSTEP HIG MED DOSW 2019. [DOI: 10.5604/01.3001.0013.6092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Autoimmunological diseases are an increasing problem nowadays in societies. Due to complex etiology, effective therapy against immune disorders is still needed. A promising alternative for the current methods of treatment can be helminthic therapy. Series of tests on animal models as well as clinical studies indicates that parasitic infection can inhibit inflammation in inflammatory bowel diseases and multiple sclerosis. Effectiveness of therapy with helminths, mainly gut nematodes depends on the activity of many compounds released during infection. Despite hopeful results, mechanisms activated by nematodes aren’t explained yet, besides, therapeutically use of live parasites is controversial. Most of studies are focused on searching parasitic factors. The use of this compound in autoimmunological diseases could be an alternative for current medicaments. The aim of current study is summarizing and discussing helminth therapy
of autoimmunological disorder on multiple sclerosis and inflammatory bowel diseases examples
as well as using parasitic compounds as a potential pharmaceutical component.
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Affiliation(s)
| | | | - Maria Doligalska
- Zakład Parazytologii, Instytut Zoologii, Wydział Biologii, Uniwersytet Warszawski, Warszawa
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19
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Poggi A, Benelli R, Venè R, Costa D, Ferrari N, Tosetti F, Zocchi MR. Human Gut-Associated Natural Killer Cells in Health and Disease. Front Immunol 2019; 10:961. [PMID: 31130953 PMCID: PMC6509241 DOI: 10.3389/fimmu.2019.00961] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 04/15/2019] [Indexed: 12/14/2022] Open
Abstract
It is well established that natural killer (NK) cells are involved in both innate and adaptive immunity. Indeed, they can recognize molecules induced at the cell surface by stress signals and virus infections. The functions of NK cells in the gut are much more complex. Gut NK cells are not precisely organized in lymphoid aggregates but rather scattered in the epithelium or in the stroma, where they come in contact with a multitude of antigens derived from commensal or pathogenic microorganisms in addition to components of microbiota. Furthermore, NK cells in the bowel interact with several cell types, including epithelial cells, fibroblasts, macrophages, dendritic cells, and T lymphocytes, and contribute to the maintenance of immune homeostasis and development of efficient immune responses. NK cells have a key role in the response to intestinal bacterial infections, primarily through production of IFNγ, which can stimulate recruitment of additional NK cells from peripheral blood leading to amplification of the anti-bacterial immune response. Additionally, NK cells can have a role in the pathogenesis of gut autoimmune inflammatory bowel diseases (IBDs), such as Crohn's Disease and Ulcerative Colitis. These diseases are considered relevant to the generation of gastrointestinal malignancies. Indeed, the role of gut-associated NK cells in the immune response to bowel cancers is known. Thus, in the gut immune system, NK cells play a dual role, participating in both physiological and pathogenic processes. In this review, we will analyze the known functions of NK cells in the gut mucosa both in health and disease, focusing on the cross-talk among bowel microenvironment, epithelial barrier integrity, microbiota, and NK cells.
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Affiliation(s)
- Alessandro Poggi
- Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Roberto Benelli
- Immunology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Roberta Venè
- Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Delfina Costa
- Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Nicoletta Ferrari
- Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Francesca Tosetti
- Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Maria Raffaella Zocchi
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
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20
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Pavlidis S, Monast C, Loza MJ, Branigan P, Chung KF, Adcock IM, Guo Y, Rowe A, Baribaud F. I_MDS: an inflammatory bowel disease molecular activity score to classify patients with differing disease-driving pathways and therapeutic response to anti-TNF treatment. PLoS Comput Biol 2019; 15:e1006951. [PMID: 31039157 PMCID: PMC6510457 DOI: 10.1371/journal.pcbi.1006951] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 05/10/2019] [Accepted: 03/13/2019] [Indexed: 02/06/2023] Open
Abstract
Crohn’s disease and ulcerative colitis are driven by both common and distinct underlying mechanisms of pathobiology. Both diseases, exhibit heterogeneity underscored by the variable clinical responses to therapeutic interventions. We aimed to identify disease-driving pathways and classify individuals into subpopulations that differ in their pathobiology and response to treatment. We applied hierarchical clustering of enrichment scores derived from gene set variation analysis of signatures representative of various immunological processes and activated cell types, to a colonic biopsy dataset that included healthy volunteers, Crohn’s disease and ulcerative colitis patients. Patient stratification at baseline or after anti-TNF treatment in clinical responders and non-responders was queried. Signatures with significantly different enrichment scores were identified using a general linear model. Comparisons to healthy controls were made at baseline in all participants and then separately in responders and non-responders. Fifty-nine percent of the signatures were commonly enriched in both conditions at baseline, supporting the notion of a disease continuum within ulcerative colitis and Crohn’s disease. Signatures included T cells, macrophages, neutrophil activation and poly:IC signatures, representing acute inflammation and a complex mix of potential disease-driving biology. Collectively, identification of significantly enriched signatures allowed establishment of an inflammatory bowel disease molecular activity score which uses biopsy transcriptomics as a surrogate marker to accurately track disease severity. This score separated diseased from healthy samples, enabled discrimination of clinical responders and non-responders at baseline with 100% specificity and 78.8% sensitivity, and was validated in an independent data set that showed comparable classification. Comparing responders and non-responders separately at baseline to controls, 43% and 70% of signatures were enriched, respectively, suggesting greater molecular dysregulation in TNF non-responders at baseline. This methodological approach could facilitate better targeted design of clinical studies to test therapeutics, concentrating on patient subsets sharing similar underlying pathobiology, therefore increasing the likelihood of clinical response. Patients exhibiting similar phenotypical characteristics, diagnosed with the same disease, exhibit variable response to therapeutics. This is a major health care issue, due to the increased patient suffering and the socioeconomical burden that occurs. Crohn’s disease and ulcerative colitis constitute good examples of inflammatory conditions, with sufferers responding differentially to existent therapeutics. Here, we identified disease-driving pathways and classified individuals into subpopulations that differ in their pathobiology and response to treatment. We utilized gene set variation analysis and transcriptomic data from inflammatory bowel disease sufferers to stratify patients at baseline or after anti-TNF treatment in clinical responders and non-responders. We explored gene signatures obtained from the literature, relevant to immune processes, which were significantly enriched in disease compared to healthy controls, as well as before and after treatment. Using these signatures, we established an inflammatory bowel disease molecular activity score, which allowed us to separate clinical responders and non-responders at baseline with high specificity and sensitivity. We validated the proposed approach in an independent data set, demonstrating comparable classification. This methodological approach may lead to better targeted design of clinical studies, allowing the selection of patient sharing similar underlying pathobiology, thus increasing the likelihood of clinical response to treatment.
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Affiliation(s)
- Stelios Pavlidis
- Janssen Research & Development Ltd, High Wycombe, United Kingdom
- National Heart and Lung Institute, Imperial College & Biomedical Research Unit, Royal Brompton & Harefield NHS Trust, London, United Kingdom
- Data Science Institute, Imperial College London, London, United Kingdom
| | - Calixte Monast
- Janssen Research & Development LLC, United States of America
| | - Matthew J. Loza
- Janssen Research & Development LLC, United States of America
| | | | - Kiang F. Chung
- National Heart and Lung Institute, Imperial College & Biomedical Research Unit, Royal Brompton & Harefield NHS Trust, London, United Kingdom
| | - Ian M. Adcock
- National Heart and Lung Institute, Imperial College & Biomedical Research Unit, Royal Brompton & Harefield NHS Trust, London, United Kingdom
| | - Yike Guo
- Data Science Institute, Imperial College London, London, United Kingdom
| | - Anthony Rowe
- Janssen Research & Development LLC, United States of America
| | - Frédéric Baribaud
- Janssen Research & Development LLC, United States of America
- * E-mail:
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21
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Intestinal Organoids as a Novel Complementary Model to Dissect Inflammatory Bowel Disease. Stem Cells Int 2019; 2019:8010645. [PMID: 31015842 PMCID: PMC6444246 DOI: 10.1155/2019/8010645] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 02/04/2019] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) include colitis ulcerosa and Crohn's disease, besides the rare microscopic colitis. Both diseases show a long-lasting, relapsing-remitting, or even chronic active course with tremendous impact on quality of life. IBDs frequently cause disability, surgical interventions, and high costs; as in other autoimmune diseases, their prevalent occurrence at an early phase of life raises the burden on health care systems. Unfortunately, our understanding of the pathogenesis is still incomplete and treatment therefore largely focuses on suppressing the resulting excessive inflammation. One obstacle for deciphering the causative processes is the scarcity of models that parallel the development of the disease, since intestinal inflammation is mostly induced artificially; moreover, the intestinal epithelium, which strongly contributes to IBD pathogenesis, is difficult to assess. Recently, the development of intestinal epithelial organoids has overcome many of those problems. Here, we give an overview on the current understanding of the pathogenesis of IBDs with reference to the limitations of previous well-established experimental models. We highlight the advantages and detriments of recent organoid-based experimental setups within the IBD field and suggest possible future applications.
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22
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Immunological Diseases of the Gastrointestinal Tract. Clin Immunol 2019. [DOI: 10.1016/b978-0-7020-6896-6.00075-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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23
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Mao YM, Zhao CN, Leng J, Leng RX, Ye DQ, Zheng SG, Pan HF. Interleukin-13: A promising therapeutic target for autoimmune disease. Cytokine Growth Factor Rev 2018; 45:9-23. [PMID: 30581068 DOI: 10.1016/j.cytogfr.2018.12.001] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 12/11/2018] [Indexed: 12/16/2022]
Abstract
Interleukin-13 (IL-13) was previously thought to be a redundant presence of IL-4, but in recent years its role in immunity, inflammation, fibrosis, and allergic diseases has become increasingly prominent. IL-13 can regulate several subtypes of T helper (Th) cells and affect their transformation, including Th1, Th2, T17, etc., thus it may play an important role in immune system. Previous studies have revealed that IL-13 is implicated in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), ulcerative colitis (UC), type 1 diabetes (T1D), sjogren's syndrome (SS), etc. In this review, we will briefly discuss the biological features of IL-13 and summarize recent advances in the role of IL-13 in the development and pathogenesis of autoimmune diseases. This information may provide new perspectives and suggestions for the selection of therapeutic targets for autoimmune diseases.
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Affiliation(s)
- Yan-Mei Mao
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, Anhui, 230032, China
| | - Chan-Na Zhao
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, Anhui, 230032, China
| | - Jing Leng
- Anhui Academy of Medical Sciences, 15 Yonghong Road, Hefei, Anhui, China
| | - Rui-Xue Leng
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, Anhui, 230032, China
| | - Dong-Qing Ye
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, Anhui, 230032, China
| | - Song Guo Zheng
- Division of Rheumatology, Penn State College of Medicine, Hershey, PA 17033, USA.
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, Anhui, 230032, China.
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Tao Y, Ai R, Hao Y, Jiang L, Dan H, Ji N, Zeng X, Zhou Y, Chen Q. Role of miR-155 in immune regulation and its relevance in oral lichen planus. Exp Ther Med 2018; 17:575-586. [PMID: 30651838 PMCID: PMC6307429 DOI: 10.3892/etm.2018.7019] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 10/04/2018] [Indexed: 02/05/2023] Open
Abstract
Oral lichen planus (OLP) is a chronic mucosal inflammatory disease. The World Health Organization has described it as a potentially malignant condition. The pathogenesis of OLP remains to be fully elucidated, but extensive evidence suggests that immunologic and inflammatory factors have important roles. MicroRNAs (miRs), which are small non-coding RNAs, have been reported to be involved in OLP. In particular, miR-155 is significantly upregulated in patients with OLP. miR-155 has numerous functions and is closely linked to inflammation and immune system regulation. However, in-depth studies of the mechanisms via which miR-155 is involved in OLP are currently insufficient. Considering the close association between miR-155 and immune regulation as well as the importance of immune factors in OLP, the role of miR-155 in the immune system was herein summarized with a focus on OLP. The present review provides a basis for further study of the molecular mechanisms underlying the development and progression of OLP.
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Affiliation(s)
- Yan Tao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ruixue Ai
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yilong Hao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lu Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hongxia Dan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ning Ji
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xin Zeng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yu Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Qianming Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Medicine of West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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25
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Feng BS, Wu YJ, Zeng XH, Yu D, Liu ZQ, Zhou CJ, Liu ZG, Zheng PY, Yang PC. Bcl2L12 mediates effects of protease-activated receptor-2 on the pathogenesis of Th2-dominated responses of patients with ulcerative colitis. Arch Biochem Biophys 2018; 657:8-14. [PMID: 30217509 DOI: 10.1016/j.abb.2018.09.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 09/03/2018] [Accepted: 09/08/2018] [Indexed: 02/06/2023]
Abstract
The immune dysregulation plays an important role in the pathogenesis of ulcerative colitis (UC). Bcl2 like protein-12 (Bcl2L12) and mast cells are involved in immune dysregulation of UC. This study aims to elucidate the role of Bcl2L12 in the contribution to the pathogenesis of T helper (Th)2-biased inflammation in UC patients. The results showed that Bcl2L12 was expressed by peripheral CD4+ T cells that was associated with Th2 polarization in UC patients. Bcl2L12 mediated the protease-activated receptor-2 (PAR2)-induced IL-4 expression in CD4+ cells. Activation of PAR2 increased expression of Bcl2L12 in CD4+ T cells. Bcl2L12 mRNA decayed spontaneously in CD4+ T cells after separated from UC patients which was prevented by activating PAR2. Bcl2L12 mediated the binding between GATA3 and the Il4 promoter in CD4+ T cells. Mice with Bcl2L12 deficiency failed to induce Th2-biased inflammation in the colon mucosa. We conclude that CD4+ T cells from UC patients expressed high levels of Bcl2L12; the latter plays an important role in the development of Th2-biased inflammation in the intestine. Bcl2L12 may be a novel therapeutic target in the treatment of Th2-biased inflammation.
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Affiliation(s)
- Bai-Sui Feng
- Department of Gastroenterology, The Second Hospital, Zhengzhou University, Zhengzhou, China
| | - Yong-Jin Wu
- The Affiliated ENT Hospital and Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Xian-Hai Zeng
- The Affiliated ENT Hospital and Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Dian Yu
- The Affiliated ENT Hospital and Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Zhi-Qiang Liu
- The Affiliated ENT Hospital and Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Cai-Jie Zhou
- Longgang Chinese Traditional Medical Hospital and Beijing University of Chinese Medicine Shenzhen Hospital, Shenzhen, China
| | - Zhi-Gang Liu
- The Affiliated ENT Hospital and Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Peng-Yuan Zheng
- Department of Gastroenterology, The Fifth Hospital, Zhengzhou University, Zhengzhou, China.
| | - Ping-Chang Yang
- The Affiliated ENT Hospital and Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China.
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26
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Fernández-Clotet A, Castro-Poceiro J, Panés J. Tofacitinib for the treatment of ulcerative colitis. Expert Rev Clin Immunol 2018; 14:881-892. [DOI: 10.1080/1744666x.2018.1532291] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Agnès Fernández-Clotet
- Inflammatory Bowel Disease Group, Institut d’Investigacions Biomètiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
| | - Jesús Castro-Poceiro
- Inflammatory Bowel Disease Group, Institut d’Investigacions Biomètiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- Department of Gastroenterology, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Julián Panés
- Inflammatory Bowel Disease Group, Institut d’Investigacions Biomètiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
- Department of Gastroenterology, Hospital Clínic de Barcelona, Barcelona, Spain
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27
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Natural killer T cells and ulcerative colitis. Cell Immunol 2018; 335:1-5. [PMID: 30638678 DOI: 10.1016/j.cellimm.2018.08.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 08/13/2018] [Accepted: 08/17/2018] [Indexed: 12/20/2022]
Abstract
Ulcerative colitis (UC) is one of the two major forms of inflammatory bowel disease (IBD). Both innate immunity and adaptive immunity are aberrant in IBD. The pathogenesis of UC includes abnormal inflammation and immune responses of the digestive tract. Natural killer T (NKT) cells participate in the innate and adaptive immune responses, together with a vast array of cytokines. Recent studies suggested that IL-13, IL5 and IL-4 are involved in the occurrence and the development of UC. Manipulating NKT cells may be a potential strategy to reconstruct the abnormal immune responses in UC. In this review, we explore the roles of NKT cells and cytokines in UC. Additionally, neutralizing antibodies and inhibitors of cytokines produced by NKT cells or their receptors are also discussed as novel therapeutic choices for UC.
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28
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Imam T, Park S, Kaplan MH, Olson MR. Effector T Helper Cell Subsets in Inflammatory Bowel Diseases. Front Immunol 2018; 9:1212. [PMID: 29910812 PMCID: PMC5992276 DOI: 10.3389/fimmu.2018.01212] [Citation(s) in RCA: 200] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/15/2018] [Indexed: 12/30/2022] Open
Abstract
The gastrointestinal tract is a site of high immune challenge, as it must maintain a delicate balance between tolerating luminal contents and generating an immune response toward pathogens. CD4+ T cells are key in mediating the host protective and homeostatic responses. Yet, CD4+ T cells are also known to be the main drivers of inflammatory bowel disease (IBD) when this balance is perturbed. Many subsets of CD4+ T cells have been identified as players in perpetuating chronic intestinal inflammation. Over the last few decades, understanding of how each subset of Th cells plays a role has dramatically increased. Simultaneously, this has allowed development of therapeutic innovation targeting specific molecules rather than broad immunosuppressive agents. Here, we review the emerging evidence of how each subset functions in promoting and sustaining the chronic inflammation that characterizes IBD.
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Affiliation(s)
- Tanbeena Imam
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Sungtae Park
- Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
| | - Mark H Kaplan
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Matthew R Olson
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States.,Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
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29
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Ahluwalia B, Moraes L, Magnusson MK, Öhman L. Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies. Scand J Gastroenterol 2018. [PMID: 29523023 DOI: 10.1080/00365521.2018.1447597] [Citation(s) in RCA: 132] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract with a multifactorial pathophysiology. Full comprehension of IBD pathology is still out of reach and, therefore, treatment is far from ideal. Nevertheless, components involved in IBD pathogenesis including environmental, genetic, microbial, and immunological factors are continuously being investigated and the improved knowledge contributes to the development of new therapies. In this article we review the aspects of the immunopathogenesis of IBD, with focus on mucosal immunity, and discuss mechanisms of action for current and emerging biological therapies.
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Affiliation(s)
- Bani Ahluwalia
- a Department of Microbiology and Immunology , University of Gothenburg, Institute for Biomedicine, Sahlgrenska Academy , Gothenburg , Sweden.,b Research Unit , Calmino Group AB , Gothenburg , Sweden
| | - Luiza Moraes
- a Department of Microbiology and Immunology , University of Gothenburg, Institute for Biomedicine, Sahlgrenska Academy , Gothenburg , Sweden
| | - Maria K Magnusson
- a Department of Microbiology and Immunology , University of Gothenburg, Institute for Biomedicine, Sahlgrenska Academy , Gothenburg , Sweden
| | - Lena Öhman
- a Department of Microbiology and Immunology , University of Gothenburg, Institute for Biomedicine, Sahlgrenska Academy , Gothenburg , Sweden.,c Department of Internal Medicine and Clinical Nutrition , University of Gothenburg, Institute for Medicine, Sahlgrenska Academy , Gothenburg , Sweden
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30
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Berkowitz L, Schultz BM, Salazar GA, Pardo-Roa C, Sebastián VP, Álvarez-Lobos MM, Bueno SM. Impact of Cigarette Smoking on the Gastrointestinal Tract Inflammation: Opposing Effects in Crohn's Disease and Ulcerative Colitis. Front Immunol 2018; 9:74. [PMID: 29441064 PMCID: PMC5797634 DOI: 10.3389/fimmu.2018.00074] [Citation(s) in RCA: 127] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Accepted: 01/11/2018] [Indexed: 01/06/2023] Open
Abstract
Cigarette smoking is a major risk factor for gastrointestinal disorders, such as peptic ulcer, Crohn’s disease (CD), and several cancers. The mechanisms proposed to explain the role of smoking in these disorders include mucosal damage, changes in gut irrigation, and impaired mucosal immune response. Paradoxically, cigarette smoking is a protective factor for the development and progression of ulcerative colitis (UC). UC and CD represent the two most important conditions of inflammatory bowel diseases, and share several clinical features. The opposite effects of smoking on these two conditions have been a topic of great interest in the last 30 years, and has not yet been clarified. In this review, we summarize the most important and well-understood effects of smoking in the gastrointestinal tract; and particularly, in intestinal inflammation, discussing available studies that have addressed the causes that would explain the opposite effects of smoking in CD and UC.
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Affiliation(s)
- Loni Berkowitz
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Bárbara M Schultz
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Geraldyne A Salazar
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Catalina Pardo-Roa
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Valentina P Sebastián
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Manuel M Álvarez-Lobos
- Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Susan M Bueno
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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31
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Jodeleit H, Palamides P, Beigel F, Mueller T, Wolf E, Siebeck M, Gropp R. Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model. J Transl Med 2017; 15:265. [PMID: 29282132 PMCID: PMC5745765 DOI: 10.1186/s12967-017-1368-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 12/15/2017] [Indexed: 11/16/2022] Open
Abstract
Background Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: ‘acute’ and ‘remodeling’ and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγnull (NSG)-UC mouse model to get a better understanding of the inflammatory processes. Methods Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined. Results Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFß1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels. Conclusions The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects. Electronic supplementary material The online version of this article (10.1186/s12967-017-1368-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Henrika Jodeleit
- Institute of Molecular Animal Breeding and Biotechnology and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377, Munich, Germany
| | - Pia Palamides
- Department of Medicinal Microbiology, Max von Pettenkofer Institute, 80336, Munich, Germany
| | - Florian Beigel
- Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Marchioninistr. 15, 81377, Munich, Germany
| | - Thomas Mueller
- Julius von Sachs Institute, University of Würzburg, 97082, Würzburg, Germany
| | - Eckhard Wolf
- Institute of Molecular Animal Breeding and Biotechnology and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377, Munich, Germany
| | - Matthias Siebeck
- Department of General- Visceral-, and Transplantation Surgery, Hospital of the University of Munich, Nussbaumstr. 20, 80336, Munich, Germany
| | - Roswitha Gropp
- Department of General- Visceral-, and Transplantation Surgery, Hospital of the University of Munich, Nussbaumstr. 20, 80336, Munich, Germany.
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32
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Beattie DT, Pulido-Rios MT, Shen F, Ho M, Situ E, Tsuruda PR, Brassil P, Kleinschek M, Hegde S. Intestinally-restricted Janus Kinase inhibition: a potential approach to maximize the therapeutic index in inflammatory bowel disease therapy. JOURNAL OF INFLAMMATION-LONDON 2017; 14:28. [PMID: 29225517 PMCID: PMC5718031 DOI: 10.1186/s12950-017-0175-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 11/22/2017] [Indexed: 12/17/2022]
Abstract
Background An unmet need remains for safe and effective treatments to induce and maintain remission in inflammatory bowel disease (IBD) patients. The Janus kinase (JAK) inhibitor, tofacitinib, has demonstrated robust efficacy in ulcerative colitis patients although, like other systemic immunosuppressants, there may be safety concerns associated with its use. This preclinical study evaluated whether modulating intestinal inflammation via local JAK inhibition can provide efficacy without systemic immunosuppression. Methods The influence of tofacitinib, dosed orally or intracecally, on oxazolone-induced colitis, oxazolone or interferon-γ (IFNγ)-induced elevation of colonic phosphorylated signal transducer and activator of transcription1 (pSTAT1) levels, and basal splenic natural killer (NK) cell counts was investigated in mice. Results Tofacitinib, dosed orally or intracecally, inhibited, with similar efficacy, oxazolone-induced colitis, represented by improvements in the disease activity index and its sub-scores (body weight, stool consistency and blood content). Intracecal dosing of tofacitinib resulted in a higher colon:plasma drug exposure ratio compared to oral dosing. At equieffective oral and intracecal doses, colonic levels of tofacitinib were similar, while the plasma levels for the latter were markedly lower, consistent with a lack of effect on splenic NK cell counts. Tofacitinib, dosed orally, intracecally, or applied to the colonic lumen in vitro, produced dose-dependent, and maximal inhibition of oxazolone or IFNγ-induced STAT1 phosphorylation in the colon. Conclusions Localized colonic JAK inhibition, by intracecal delivery of tofacitinib, provides colonic target engagement and efficacy in a mouse colitis model at doses which do not impact splenic NK cell counts. Intestinal targeting of JAK may permit separation of local anti-inflammatory activity from systemic immunosuppression, and thus provide a larger therapeutic index compared to systemic JAK inhibitors.
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Affiliation(s)
- David T Beattie
- Department of Pharmacology , Theravance Biopharma US, Inc, 901 Gateway Boulevard, South San Francisco, CA 94080 USA
| | - M Teresa Pulido-Rios
- Department of Pharmacology , Theravance Biopharma US, Inc, 901 Gateway Boulevard, South San Francisco, CA 94080 USA
| | - Fei Shen
- Department of Pharmacology , Theravance Biopharma US, Inc, 901 Gateway Boulevard, South San Francisco, CA 94080 USA
| | - Melissa Ho
- Department of Biology, Theravance Biopharma US, Inc, 901 Gateway Boulevard, South San Francisco, CA 94080 USA
| | - Eva Situ
- Department of Biology, Theravance Biopharma US, Inc, 901 Gateway Boulevard, South San Francisco, CA 94080 USA
| | - Pam R Tsuruda
- Department of Pharmacology , Theravance Biopharma US, Inc, 901 Gateway Boulevard, South San Francisco, CA 94080 USA
| | - Patrick Brassil
- Department of Drug Metabolism and Pharmacokinetics, Theravance Biopharma US, Inc, 901 Gateway Boulevard, South San Francisco, CA 94080 USA
| | - Melanie Kleinschek
- Department of Biology, Theravance Biopharma US, Inc, 901 Gateway Boulevard, South San Francisco, CA 94080 USA
| | - Sharath Hegde
- Department of Pharmacology , Theravance Biopharma US, Inc, 901 Gateway Boulevard, South San Francisco, CA 94080 USA
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Zundler S, Schillinger D, Fischer A, Atreya R, López-Posadas R, Watson A, Neufert C, Atreya I, Neurath MF. Blockade of αEβ7 integrin suppresses accumulation of CD8 + and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo. Gut 2017; 66:1936-1948. [PMID: 27543429 DOI: 10.1136/gutjnl-2016-312439] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 07/21/2016] [Accepted: 07/24/2016] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Therapeutically targeting lymphocyte adhesion is of increasing relevance in IBD. Yet, central aspects of the action of antiadhesion compounds are incompletely understood. We investigated the role of αEβ7 and α4β7 integrins and their blockade by vedolizumab and etrolizumab for trafficking of IBD T lymphocytes in an in vivo model of homing to and retention in the inflamed gut. DESIGN We explored integrin expression in patients with IBD by flow cytometry and immunohistochemistry, while regulation of integrins was studied in T cell cultures. The functional relevance of integrins was assessed by adhesion assays and a recently established humanised mouse model in dextran sodium sulfate-treated immunodeficient mice. RESULTS High expression of αEβ7 was noted on CD8+ and CD4+ Th9 cells, while α4β7 was expressed on CD8+, Th2 and Th17 cells. T cell receptor stimulation and transforming growth factor β were key inducers of αEβ7 on human T cells, while butyric acid suppressed αEβ7. In comparison to α4β7 blockade via vedolizumab, blockade of β7 via etrolizumab surrogate antibody superiorly reduced colonic numbers of CD8+ and Th9 cells in vivo after 3 hours, while no difference was noted after 0.5 hours. AEβ7 expression was higher on CD8+ T cells from patients with IBD under vedolizumab therapy. CONCLUSIONS AEβ7 is of key relevance for gut trafficking of IBD CD8+ T cells and CD4+ Th9 cells in vivo and mainly retention might account for this effect. These findings indicate that blockade of αEβ7 in addition to α4β7 may be particularly effective in intestinal disorders with expansion of CD8+ and Th9 cells such as IBD.
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Affiliation(s)
- Sebastian Zundler
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Daniela Schillinger
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Anika Fischer
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Raja Atreya
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Rocío López-Posadas
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Alastair Watson
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Clemens Neufert
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Imke Atreya
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
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Abstract
Type 2 immunity is characterized by the production of IL-4, IL-5, IL-9 and IL-13, and this immune response is commonly observed in tissues during allergic inflammation or infection with helminth parasites. However, many of the key cell types associated with type 2 immune responses - including T helper 2 cells, eosinophils, mast cells, basophils, type 2 innate lymphoid cells and IL-4- and IL-13-activated macrophages - also regulate tissue repair following injury. Indeed, these cell populations engage in crucial protective activity by reducing tissue inflammation and activating important tissue-regenerative mechanisms. Nevertheless, when type 2 cytokine-mediated repair processes become chronic, over-exuberant or dysregulated, they can also contribute to the development of pathological fibrosis in many different organ systems. In this Review, we discuss the mechanisms by which type 2 immunity contributes to tissue regeneration and fibrosis following injury.
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Affiliation(s)
- Richard L Gieseck
- Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20852, USA
| | - Mark S Wilson
- Immunology Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
| | - Thomas A Wynn
- Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20852, USA
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35
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Buzza MS, Johnson TA, Conway GD, Martin EW, Mukhopadhyay S, Shea-Donohue T, Antalis TM. Inflammatory cytokines down-regulate the barrier-protective prostasin-matriptase proteolytic cascade early in experimental colitis. J Biol Chem 2017; 292:10801-10812. [PMID: 28490634 DOI: 10.1074/jbc.m116.771469] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 05/02/2017] [Indexed: 12/17/2022] Open
Abstract
Compromised gastrointestinal barrier function is strongly associated with the progressive and destructive pathologies of the two main forms of irritable bowel disease (IBD), ulcerative colitis (UC), and Crohn's disease (CD). Matriptase is a membrane-anchored serine protease encoded by suppression of tumorigenicity-14 (ST14) gene, which is critical for epithelial barrier development and homeostasis. Matriptase barrier-protective activity is linked with the glycosylphosphatidylinositol (GPI)-anchored serine protease prostasin, which is a co-factor for matriptase zymogen activation. Here we show that mRNA and protein expression of both matriptase and prostasin are rapidly down-regulated in the initiating inflammatory phases of dextran sulfate sodium (DSS)-induced experimental colitis in mice, and, significantly, the loss of these proteases precedes the appearance of clinical symptoms, suggesting their loss may contribute to disease susceptibility. We used heterozygous St14 hypomorphic mice expressing a promoter-linked β-gal reporter to show that inflammatory colitis suppresses the activity of the St14 gene promoter. Studies in colonic T84 cell monolayers revealed that barrier disruption by the colitis-associated Th2-type cytokines, IL-4 and IL-13, down-regulates matriptase as well as prostasin through phosphorylation of the transcriptional regulator STAT6 and that inhibition of STAT6 with suberoylanilide hydroxamic acid (SAHA) restores protease expression and reverses cytokine-induced barrier dysfunction. Both matriptase and prostasin are significantly down-regulated in colonic tissues from human subjects with active ulcerative colitis or Crohn's disease, implicating the loss of this barrier-protective protease pathway in the pathogenesis of irritable bowel disease.
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Affiliation(s)
- Marguerite S Buzza
- From the Center for Vascular and Inflammatory Diseases and Department of Physiology and
| | - Tierra A Johnson
- From the Center for Vascular and Inflammatory Diseases and Department of Physiology and
| | - Gregory D Conway
- From the Center for Vascular and Inflammatory Diseases and Department of Physiology and
| | - Erik W Martin
- From the Center for Vascular and Inflammatory Diseases and Department of Physiology and
| | | | - Terez Shea-Donohue
- the Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland 21201
| | - Toni M Antalis
- From the Center for Vascular and Inflammatory Diseases and Department of Physiology and
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Kotredes KP, Thomas B, Gamero AM. The Protective Role of Type I Interferons in the Gastrointestinal Tract. Front Immunol 2017; 8:410. [PMID: 28428788 PMCID: PMC5382159 DOI: 10.3389/fimmu.2017.00410] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 03/22/2017] [Indexed: 12/18/2022] Open
Abstract
The immune system of the gastrointestinal (GI) tract manages the significant task of recognizing and eliminating pathogens while maintaining tolerance of commensal bacteria. Dysregulation of this delicate balance can be detrimental, resulting in severe inflammation, intestinal injury, and cancer. Therefore, mechanisms to relay important signals regulating cell growth and immune reactivity must be in place to support GI homeostasis. Type I interferons (IFN-I) are a family of pleiotropic cytokines, which exert a wide range of biological effects including promotion of both pro- and anti-inflammatory activities. Using animal models of colitis, investigations into the regulation of intestinal epithelium inflammation highlight the role of IFN-I signaling during fine modulation of the immune system. The intestinal epithelium of the gut guides the immune system to differentiate between commensal and pathogenic microbiota, which relies on intimate links with the IFN-I signal-transduction pathway. The current paradigm depicts an IFN-I-induced antiproliferative state in the intestinal epithelium enabling cell differentiation, cell maturation, and proper intestinal barrier function, strongly supporting its role in maintaining baseline immune activity and clearance of damaged epithelia or pathogens. In this review, we will highlight the importance of IFN-I in intestinal homeostasis by discussing its function in inflammation, immunity, and cancer.
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Affiliation(s)
- Kevin P Kotredes
- Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, PA, USA
| | - Brianna Thomas
- Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, PA, USA
| | - Ana M Gamero
- Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, PA, USA
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Park JH, Peyrin-Biroulet L, Eisenhut M, Shin JI. IBD immunopathogenesis: A comprehensive review of inflammatory molecules. Autoimmun Rev 2017; 16:416-426. [PMID: 28212924 DOI: 10.1016/j.autrev.2017.02.013] [Citation(s) in RCA: 211] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 01/19/2017] [Indexed: 02/06/2023]
Abstract
Inflammatory molecules play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease, both of which are chronic inflammatory conditions of the gastrointestinal tract. Abnormal expressions of pro- and anti-inflammatory molecules have been described to cause an imbalance to the gut innate and adaptive immunity, and recently a large portion of research in IBD has been geared towards identifying novel molecules that may be used as potential therapeutic targets. Understanding of these inflammatory molecules has suggested that although ulcerative colitis and Crohn's disease share many common clinical symptoms and signs, they are in fact two separate clinical entities characterized by different immunopathogenesis. In this review, we comprehensively discuss the roles of numerous inflammatory molecules including but not limited to cytokines, chemokines, inflammasomes, microRNAs and neuropeptides and their expression status in ulcerative colitis and Crohn's disease in relation to their effects on the overall intestinal inflammatory process.
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Affiliation(s)
- Jae Hyon Park
- Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea
| | - Laurent Peyrin-Biroulet
- Inserm U954 and Department of Gastroenterology, Nancy University Hospital, Université de Lorraine, France
| | - Michael Eisenhut
- Department of Paediatrics, Luton & Dunstable University Hospital NHS Foundation Trust, Lewsey Road, Luton, LU40DZ, United Kingdom
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Republic of Korea.
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Bilsborough J, Targan SR, Snapper SB. Therapeutic Targets in Inflammatory Bowel Disease: Current and Future. ACTA ACUST UNITED AC 2016. [DOI: 10.1038/ajgsup.2016.18] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Fischer A, Zundler S, Atreya R, Rath T, Voskens C, Hirschmann S, López-Posadas R, Watson A, Becker C, Schuler G, Neufert C, Atreya I, Neurath MF. Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo. Gut 2016; 65:1642-1664. [PMID: 26209553 PMCID: PMC5036234 DOI: 10.1136/gutjnl-2015-310022] [Citation(s) in RCA: 129] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 06/22/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Gut homing of lymphocytes via adhesion molecules has recently emerged as new target for therapy in IBDs. We aimed to analyse the in vivo homing of effector (Teff) and regulatory (Treg) T cells to the inflamed gut via α4β7 and G protein receptor GPR15. DESIGN We assessed the expression of homing receptors on T cells in peripheral blood and inflamed mucosa. We studied the migration pattern and homing of Teff and Treg cells to the inflamed gut using intravital confocal microscopy and FACS in a humanised mouse model in dextran sodium sulfate-treated NSG (NOD.Cg-Prkdcscid-Il2rgtm1Wjl/SzJ) mice. RESULTS Expression of GPR15 and α4β7 was significantly increased on Treg rather than Teff cells in peripheral blood of patients with UC as compared with Crohn's disease and controls. In vivo analysis in a humanised mouse model showed augmented gut homing of UC Treg cells as compared with controls. Moreover, suppression of UC (but not control) Teff and Treg cell homing was noted upon treatment with the α4β7 antibody vedolizumab. In contrast, siRNA blockade of GPR15 had only effects on homing of Teff cells but did not affect Treg homing in UC. Clinical vedolizumab treatment was associated with marked expansion of UC Treg cells in peripheral blood. CONCLUSIONS α4β7 rather than GPR15 is crucial for increased colonic homing of UC Treg cells in vivo, while both receptors control UC Teff cell homing. Vedolizumab treatment impairs homing of UC Treg cells leading to their accumulation in peripheral blood with subsequent suppression of systemic Teff cell expansion.
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Affiliation(s)
- Anika Fischer
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Sebastian Zundler
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Raja Atreya
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Timo Rath
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Caroline Voskens
- Department of Dermatology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Simon Hirschmann
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Rocío López-Posadas
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Alastair Watson
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Christoph Becker
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Gerold Schuler
- Department of Dermatology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Clemens Neufert
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Imke Atreya
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
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Park JH, Jeong DY, Peyrin-Biroulet L, Eisenhut M, Shin JI. Insight into the role of TSLP in inflammatory bowel diseases. Autoimmun Rev 2016; 16:55-63. [PMID: 27697608 DOI: 10.1016/j.autrev.2016.09.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 08/08/2016] [Indexed: 12/22/2022]
Abstract
Proinflammatory cytokines are thought to modulate pathogeneses of various inflammatory bowel diseases (IBDs). Thymic stromal lymphopoietin (TSLP), which has been studied in various allergic diseases such as asthma, atopic dermatitis (AD) and eosinophilic esophagitis (EoE), has been less considered to be involved in IBDs. However, mucosal dendritic cells (DCs) induced by various cytokines including TSLP were reported to cause polarization of T cell toward Th2 response, the differentiation of regulatory T-cell (Treg), and secretion of IgA by B cells. In this review, we discuss the concept that decreased TSLP has the potential to accelerate the development of Th1 response dominant diseases such as the Crohn's disease (CD) while increased TSLP has the potential to lead to a development of Th2 cell dominant diseases such the ulcerative colitis (UC). To examine TSLP's role as a potential determining factor for differentiating UC and CD, we analyzed the effects of other genes regulated by TSLP in regards to the UC and CD pathogeneses using data from online open access resources such as NetPath, GeneMania, and the String database. Our findings indicate that TSLP is a key mediator in the pathogenesis of IBDs and that further studies are needed to evaluate its role.
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Affiliation(s)
| | | | - Laurent Peyrin-Biroulet
- Inserm U954 and Department of Gastroenterology, Nancy University Hospital, Université de Lorraine, France
| | - Michael Eisenhut
- Luton & Dunstable University Hospital NHS Foundation Trust, Luton, United Kingdom
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea.
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Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets. Transl Res 2016; 176:38-68. [PMID: 27220087 DOI: 10.1016/j.trsl.2016.04.009] [Citation(s) in RCA: 134] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 03/17/2016] [Accepted: 04/28/2016] [Indexed: 12/14/2022]
Abstract
Ulcerative colitis and Crohn's disease are the 2 major phenotypes of inflammatory bowel disease (IBD), which are influenced by a complex interplay of immunological and genetic elements, though the precise etiology still remains unknown. With IBD developing into a globally prevailing disease, there is a need to explore new targets and a thorough understanding of the pathophysiological differences between the healthy and diseased gut could unearth new therapeutic opportunities. In this review, we provide an overview of the major aspects of IBD pathogenesis and thereafter present a comprehensive analysis of the gut pathophysiology leading to a discussion on some of the most promising targets and biologic therapies currently being explored. These include various gut proteins (CXCL-10, GATA-3, NKG2D, CD98, microRNAs), immune cells recruited to the gut (mast cells, eosinophils, toll-like receptors 2, 4), dysregulated proinflammatory cytokines (interleukin-6, -13, -18, -21), and commensal microbiota (probiotics and fecal microbiota transplantation). We also evaluate some of the emerging nonconventional therapies being explored in IBD treatment focusing on the latest developments in stem cell research, oral targeting of the gut-associated lymphoid tissue, novel anti-inflammatory signaling pathway targeting, adenosine deaminase inhibition, and the beneficial effects of antioxidant and nutraceutical therapies. In addition, we highlight the growth of biologics and their targets in IBD by providing information on the preclinical and clinical development of over 60 biopharmaceuticals representing the state of the art in ulcerative colitis and Crohn's disease drug development.
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de Paula-Silva M, Barrios BE, Macció-Maretto L, Sena AA, Farsky SHP, Correa SG, Oliani SM. Role of the protein annexin A1 on the efficacy of anti-TNF treatment in a murine model of acute colitis. Biochem Pharmacol 2016; 115:104-13. [PMID: 27343762 DOI: 10.1016/j.bcp.2016.06.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 06/17/2016] [Indexed: 02/08/2023]
Abstract
TNF-α is involved in the mechanisms that initiate inflammatory bowel diseases (IBDs). Anti-TNF-α drugs, such as infliximab (IFX), cause non-responsiveness and side effects, indicating the need to investigate alternative therapies for these diseases. The anti-inflammatory protein, annexin A1 (AnxA1), has been associated with the protection of the gastrointestinal mucosa. To further address the role of endogenous AnxA1 on the TNF-α blockade efficacy in a murine model, we assessed colitis induced by Dextran Sulfate Sodium (DSS) in wild-type (WT) and AnxA1(-/-) Balb/c mice treated with IFX. We consistently observed endogenous AnxA1 prevented clinical and physiological manifestations of experimental colitis treated with IFX, additionally the manifestation of the disease was observed earlier in AnxA1(-)(/-) mice. Rectal bleeding, diarrhea, histological score, epithelial damages and collagen degradation caused by DSS were prevented following IFX treatment only in WT mice. IL-6 increased during colitis in WT and AnxA1(-)(/-) mice, decreasing under IFX treatment in WT. The influx of neutrophils and TNF-α secretion were largely elevated in AnxA1(-)(/-) mice when compared to WT mice. In the group WT/DSS+IFX, phagocytes were more susceptible to apoptosis following treatment with IFX. Endogenous expression of AnxA1 increased after DSS and decreased with IFX treatment, demonstrating an attenuated inflammatory response. The data indicate that AnxA1 contributes to the establishment of intestinal homeostasis after blocking of TNF-α was used as a treatment of IBD, constituting a key molecule in the mechanism of action and a potential biomarker of therapeutic efficacy.
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Affiliation(s)
- Marina de Paula-Silva
- Post-graduation in Structural and Functional Biology, São Paulo Federal University (UNIFESP), São Paulo, São Paulo, Brazil
| | - Bibiana Elisabeth Barrios
- Center of Investigation in Biochemistry and Clinical Immunology, Cordoba National University (UNC), Córdoba, Córdoba, Argentina
| | - Lisa Macció-Maretto
- Center of Investigation in Biochemistry and Clinical Immunology, Cordoba National University (UNC), Córdoba, Córdoba, Argentina
| | - Angela Aparecida Sena
- Department of Biology, Laboratory of Immunomorphology, São Paulo State University (UNESP), São José do Rio Preto, São Paulo, Brazil
| | | | - Silvia Graciela Correa
- Center of Investigation in Biochemistry and Clinical Immunology, Cordoba National University (UNC), Córdoba, Córdoba, Argentina
| | - Sonia Maria Oliani
- Post-graduation in Structural and Functional Biology, São Paulo Federal University (UNIFESP), São Paulo, São Paulo, Brazil; Department of Biology, Laboratory of Immunomorphology, São Paulo State University (UNESP), São José do Rio Preto, São Paulo, Brazil.
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Hinks TSC. Mucosal-associated invariant T cells in autoimmunity, immune-mediated diseases and airways disease. Immunology 2016; 148:1-12. [PMID: 26778581 PMCID: PMC4819138 DOI: 10.1111/imm.12582] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 12/21/2015] [Accepted: 01/05/2016] [Indexed: 12/11/2022] Open
Abstract
Mucosal-associated invariant T (MAIT) cells are a novel class of innate-like T cells, expressing a semi-invariant T-cell receptor (TCR) and able to recognize small molecules presented on the non-polymorphic MHC-related protein 1. Their intrinsic effector-memory phenotype, enabling secretion of pro-inflammatory cytokines, and their relative abundance in humans imply a significant potential to contribute to autoimmune processes. However, as MAIT cells were unknown until recently and specific immunological tools were unavailable, little is known of their roles in disease. Here I review observations from clinical studies and animal models of autoimmune and immune-mediated diseases including the roles of MAIT cells in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and airways diseases. MAIT cell deficiencies are frequently observed in peripheral blood, and at sites of disease such as the airways in asthma. However, MAIT cells have a specific sensitivity to suppression by therapeutic corticosteroids that may confound many of these observations, as may the tendency of the surface marker CD161 to activation-induced down-regulation. Nonetheless, the dependence on bacteria for the development of MAIT cells suggests a potentially important protective role linking the influences of early life microbial exposures and subsequent development of autoimmunity. Conversely, MAIT cells could contribute to chronic inflammation either through TCR-independent activation, or potentially by TCR recognition of as yet undiscovered ligands. Future research will be greatly facilitated by the immunological tools that are now available, including murine genetic models and human and murine specific tetramers.
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Affiliation(s)
- Timothy S C Hinks
- Department for Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.,Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, UK.,NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, UK
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Xu Z, Wei C, Zhang RU, Yao J, Zhang D, Wang L. Epigallocatechin-3-gallate-induced inhibition of interleukin-6 release and adjustment of the regulatory T/T helper 17 cell balance in the treatment of colitis in mice. Exp Ther Med 2015; 10:2231-2238. [PMID: 26668622 DOI: 10.3892/etm.2015.2824] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Accepted: 01/05/2015] [Indexed: 12/13/2022] Open
Abstract
Epigallocatechin-3-gallate (EGCG) has a promising therapeutic effect for ulcerative colitis (UC), but the treatment mechanism has yet to be fully elucidated. The aim of the present study was to investigate the mechanism of EGCG in the treatment of UC. Experimental colitis mouse models were prepared. The mice were randomly divided into four groups: Normal control, model (MD), 50 mg/kg/day EGCG treatment and 100 mg/kg/day EGCG treatment. The daily disease activity index (DAI) of the mice was recorded, changes in the organizational structure of the colon were observed and the spleen index (SI) was measured. In addition, levels of interleukin (IL)-6, IL-10, IL-17 and transforming growth factor (TGF)-β1 in the plasma and hypoxia-inducible factor (HIF)-1α and signal transducer and activator of transcription (STAT) 3 protein expression in colon tissues were evaluated. Compared with the MD group, the mice in the two EGCG treatment groups exhibited decreased DAIs and SIs and an attenuation in the colonic tissue erosion. EGCG could reduce the release of IL-6 and IL-17 and regulate the mouse splenic regulatory T-cell (Treg)/T helper 17 cell (Th17) ratio, while increasing the plasma levels of IL-10 and TGF-β1 and decreasing the HIF-1α and STAT3 protein expression in the colon. The experiments confirmed that EGCG treated mice with experimental colitis by inhibiting the release of IL-6 and regulating the body Treg/Th17 balance.
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Affiliation(s)
- Zhenglei Xu
- Department of Gastroenterology, Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518000, P.R. China
| | - Cheng Wei
- Department of Gastroenterology, Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518000, P.R. China
| | - R U Zhang
- Department of Gastroenterology, Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518000, P.R. China
| | - Jun Yao
- Department of Gastroenterology, Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518000, P.R. China
| | - Dinguo Zhang
- Department of Gastroenterology, Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518000, P.R. China
| | - Lisheng Wang
- Department of Gastroenterology, Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518000, P.R. China
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Abstract
BACKGROUND Crohn's disease (CD) and ulcerative colitis (UC) are the major forms of inflammatory bowel disease, and pathogenesis involves a complex interplay among genetic, environmental, and immunological factors. We evaluated isoform expression of the IL-12-activated transcription factor STAT4 in children with CD and UC. METHODS We collected biopsy samples from both patients newly diagnosed with CD and with UC. We further collected blood samples from patients newly diagnosed with CD and with UC as well as from patients who had a flare-up after being in clinical remission, and we examined the ratios of STAT4β/STAT4α mRNA. In addition to STAT4 isoforms, we measured the expression of the cytokines TNFα, IFNγ, granulocyte macrophage-colony stimulating factor, and IL-17 using polymerase chain reaction of biopsy samples and multiplex analysis of patient serum samples. RESULTS Ratios of STAT4β/STAT4α were increased in specific gastrointestinal tract segments in both patients with CD and those with UC that correlate with the location and severity of inflammation. In contrast, we did not observe changes in STAT4β/STAT4α ratios in biopsy specimens from patients with eosinophilic esophagitis. We also observed increased STAT4β/STAT4α ratios in the peripheral blood mononuclear cells of patients with UC and those with CD, compared with healthy controls. Ratios were normalized after patients were treated with steroids. CONCLUSIONS Collectively, these data indicate that STAT4 isoforms could be an important noninvasive biomarker in the diagnosis and treatment of inflammatory bowel disease and that expression of these isoforms might provide further insight into the pathogenesis of IBD.
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Abstract
Interleukin-13 (IL-13) is an immunosuppressive cytokine produced by several immune cells and cancer cells. The aim of this retrospective study was to determine if serum IL-13 levels have an association with clinical outcome in patients with colorectal cancer. A total of 241 patients with colorectal cancer were enrolled in the present study. Preoperative serum IL-13 concentrations were measured by enzyme-linked immunosorbent assay. We analyzed the association of serum IL-13 levels with clinicopathological variables. Patients with lymph node metastasis, lymphatic invasion, vascular invasion, distant metastases or advanced stage of disease had significantly lower serum IL-13 levels. Low serum IL-13 was significantly associated with both poor recurrence-free and overall survival. Multivariate analysis showed that low IL-13 levels were an independent predictive marker for poor prognosis. In conclusion, our data suggest that low serum IL-13 levels may be a useful predictive marker for poor prognosis in colorectal cancer.
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Combinatorial Intervention with Mesenchymal Stem Cells and Granulocyte Colony-Stimulating Factor in a Rat Model of Ulcerative Colitis. Dig Dis Sci 2015; 60:1948-57. [PMID: 25894931 DOI: 10.1007/s10620-015-3655-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Accepted: 03/30/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND Bone marrow mesenchymal stem cells sometimes improve symptoms of inflammatory bowel disease. AIM To test the effects of combined granulocyte colony-stimulating factor (G-CSF) and MSC therapy in a rat model of ulcerative colitis (UC). METHODS Seventy-two rats with TNBS-induced UC were divided into control or treatment groups: control (no disease and no treatment), no treatment (model), 5-aminosalicylate (5-ASA) enema, or MSCs (labeled with BrdU) with (MSC/GCSF) or without (MSC) G-CSF, and G-CSF alone (GCSF). On days 14 and 28 post-treatment, macroscopic and histological appearances were assessed and the disease activity index (DAI) scored to evaluate the severity of disease. BrdU-labeled MSCs were identified by immunofluorescence to confirm transplantation and their location. The inflammatory profile of each group was evaluated by measuring expression of nuclear NF-κB p65, serum TNF-α, and IL-10 and by activity of mucosal myeloperoxidase (MPO). RESULTS Rats receiving MSC and G-CSF combination therapy had increased recruitment of MSCs to the colonic mucosa compared with rats receiving MSC transplantation alone. On day 28, the DAI, MPO activity, serum TNF-α and IL-10 levels, and NF-κB p65 expression in the combination therapy group were significantly lower compared to animals receiving no treatment, MSCs alone, or G-CSF alone (P < 0.05). CONCLUSION Intravenously transplanted MSCs migrate and distribute to the colon to effectively alleviate the symptoms of UC, while G-CSF enhances this effect via an anti-inflammatory effect and improvement in the pathologic features of UC. G-CSF may be a promising therapeutic regulator of MSCs that can improve therapeutic outcomes in patients with UC.
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McKay DM. Not all parasites are protective. Parasite Immunol 2015; 37:324-32. [DOI: 10.1111/pim.12160] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 11/09/2014] [Indexed: 12/11/2022]
Affiliation(s)
- Derek M. McKay
- Department of Physiology and Pharmacology; Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases; Gastrointestinal Research Group and Inflammation Research Network; Cumming School of Medicine, University of Calgary; Calgary AB Canada
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Danese S, Rudziński J, Brandt W, Dupas JL, Peyrin-Biroulet L, Bouhnik Y, Kleczkowski D, Uebel P, Lukas M, Knutsson M, Erlandsson F, Hansen MB, Keshav S. Tralokinumab for moderate-to-severe UC: a randomised, double-blind, placebo-controlled, phase IIa study. Gut 2015; 64:243-9. [PMID: 25304132 DOI: 10.1136/gutjnl-2014-308004] [Citation(s) in RCA: 128] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Interleukin-13 (IL-13) has been implicated as a key driver of UC. This trial evaluates the efficacy and safety of tralokinumab, an IL-13-neutralising antibody, as add-on therapy in adults with moderate-to-severe UC despite standard treatments. DESIGN Non-hospitalised adults with UC (total Mayo score ≥6) were randomised to receive tralokinumab 300 mg or placebo subcutaneously every 2 weeks for 12 weeks. The primary end point was the rate of clinical response at week 8. Secondary efficacy end points included clinical remission and mucosal healing rates at week 8 and changes in total Mayo score, total modified Riley score, partial Mayo score and disease activity markers. RESULTS Clinical response rate was 38% (21/56) for tralokinumab vs. 33% (18/55) for placebo (p=0.406). Clinical remission rate was 18% (10/56) vs. 6% (3/55) (p=0.033) and mucosal healing rate was 32% (18/56) vs. 20% (11/55) (p=0.104) for tralokinumab vs placebo. Changes to week 8 in total Mayo score and total modified Riley score were similar for tralokinumab and placebo (least-squares mean difference between groups: -0.49 (p=0.394) and 0.25 (p=0.449), respectively). Partial Mayo score at week 4 was lower with tralokinumab than placebo (least-squares mean difference between groups: -0.90 (p=0.041)). No consistent patterns were observed for disease activity markers. Tralokinumab had an acceptable safety profile. CONCLUSIONS Add-on therapy with tralokinumab did not significantly improve clinical response. However, the higher clinical remission rate with tralokinumab than placebo suggests that tralokinumab may benefit some patients with UC. Tralokinumab was well tolerated. TRIAL REGISTRATION NUMBER ClinicalTrials.gov number: NCT01482884.
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Affiliation(s)
| | | | | | | | - Laurent Peyrin-Biroulet
- Inserm U954 and Department of Gastroenterology, Université de Lorraine, Vandœuvre-lès-Nancy, France
| | | | | | - Peter Uebel
- P. Uebel Haus der Gesundheit, Ludwigshafen, Germany
| | - Milan Lukas
- IBD Clinical and Research Centre, ISCARE Lighthouse and 1st Medical Faculty, Charles University, Prague, Czech Republic
| | | | | | | | - Satish Keshav
- Department of Medicine, John Radcliffe Hospital, Oxford, UK
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Onitake T, Ueno Y, Tanaka S, Sagami S, Hayashi R, Nagai K, Hide M, Chayama K. Pulverized konjac glucomannan ameliorates oxazolone-induced colitis in mice. Eur J Nutr 2014; 54:959-69. [DOI: 10.1007/s00394-014-0772-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 08/01/2014] [Indexed: 01/08/2023]
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