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Xiao Z, Xie J, Zhao X, Chen X, Lu Y, Xu Y, Wu M, An L, Li Q. Role of Pyroptosis in inflammatory bowel disease. Int Immunopharmacol 2025; 155:114619. [PMID: 40209313 DOI: 10.1016/j.intimp.2025.114619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 03/21/2025] [Accepted: 04/03/2025] [Indexed: 04/12/2025]
Abstract
Inflammatory bowel disease (IBD) is a serious chronic condition marked by persistent and recurrent intestinal ulcers. Although the exact cause of IBD remains unclear, it is generally accepted that a complex interaction among dietary factors, gut microbiota, and immune responses in genetically predisposed individuals contributes to its development. Pyroptosis, an inflammatory form of programmed cell death activated by inflammasomes, is marked by the rupture of cell membranes and the subsequent release of inflammatory mediators. Emerging evidence indicates that pyroptosis plays a crucial role in the pathogenesis of IBD. Moderate pyroptosis activation can enhance intestinal immune defenses, while excessive inflammasome activation can trigger an inflammatory cascade, resulting in increased damage to intestinal tissues. This article reviews the molecular mechanisms underlying pyroptosis and highlights its role in the onset and progression of IBD. Furthermore, We explore recent advancements in IBD treatment, focusing on small molecule compounds that specifically target and inhibit pyroptosis.
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Affiliation(s)
- Zhiyi Xiao
- The Clinical Medical College, Guizhou Medical University, Guiyang 550004, China
| | - Jiling Xie
- The Clinical Medical College, Guizhou Medical University, Guiyang 550004, China
| | - Xun Zhao
- Department of Gastroenterology, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China
| | - Xiangjun Chen
- The Clinical Medical College, Guizhou Medical University, Guiyang 550004, China
| | - Yihong Lu
- The Clinical Medical College, Guizhou Medical University, Guiyang 550004, China
| | - Yuanzhao Xu
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China
| | - Manqing Wu
- Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China
| | - Lingyue An
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China.
| | - Qing Li
- Department of Gastroenterology and Surgery, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China.
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Kaden T, Alonso‐Román R, Stallhofer J, Gresnigt MS, Hube B, Mosig AS. Leveraging Organ-on-Chip Models to Investigate Host-Microbiota Dynamics and Targeted Therapies for Inflammatory Bowel Disease. Adv Healthc Mater 2025; 14:e2402756. [PMID: 39491534 PMCID: PMC12004439 DOI: 10.1002/adhm.202402756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/29/2024] [Indexed: 11/05/2024]
Abstract
Inflammatory bowel disease (IBD) is an idiopathic gastrointestinal disease with drastically increasing incidence rates. Due to its multifactorial etiology, a precise investigation of the pathogenesis is extremely difficult. Although reductionist cell culture models and more complex disease models in animals have clarified the understanding of individual disease mechanisms and contributing factors of IBD in the past, it remains challenging to bridge research and clinical practice. Conventional 2D cell culture models cannot replicate complex host-microbiota interactions and stable long-term microbial culture. Further, extrapolating data from animal models to patients remains challenging due to genetic and environmental diversity leading to differences in immune responses. Human intestine organ-on-chip (OoC) models have emerged as an alternative in vitro model approach to investigate IBD. OoC models not only recapitulate the human intestinal microenvironment more accurately than 2D cultures yet may also be advantageous for the identification of important disease-driving factors and pharmacological interventions targets due to the possibility of emulating different complexities. The predispositions and biological hallmarks of IBD focusing on host-microbiota interactions at the intestinal mucosal barrier are elucidated here. Additionally, the potential of OoCs to explore microbiota-related therapies and personalized medicine for IBD treatment is discussed.
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Affiliation(s)
- Tim Kaden
- Dynamic42 GmbH07745JenaGermany
- Institute of Biochemistry IICenter for Sepsis Control and CareJena University Hospital07747JenaGermany
| | - Raquel Alonso‐Román
- Department of Microbial Pathogenicity MechanismsLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
- Junior Research Group Adaptive Pathogenicity StrategiesLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
| | | | - Mark S. Gresnigt
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
- Junior Research Group Adaptive Pathogenicity StrategiesLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
| | - Bernhard Hube
- Department of Microbial Pathogenicity MechanismsLeibniz Institute for Natural Product Research and Infection Biology – Hans‐Knöll‐Institute07745JenaGermany
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
- Institute of MicrobiologyFaculty of Biological SciencesFriedrich Schiller University07743JenaGermany
| | - Alexander S. Mosig
- Institute of Biochemistry IICenter for Sepsis Control and CareJena University Hospital07747JenaGermany
- Cluster of Excellence Balance of the MicroverseFriedrich Schiller University Jena07745JenaGermany
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3
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Dalal R, Sadhu S, Batra A, Goswami S, Dandotiya J, K V V, Yadav R, Singh V, Chaturvedi K, Kannan R, Kumar S, Kumar Y, Rathore DK, Salunke DB, Ahuja V, Awasthi A. Gut commensals-derived succinate impels colonic inflammation in ulcerative colitis. NPJ Biofilms Microbiomes 2025; 11:44. [PMID: 40082467 PMCID: PMC11906746 DOI: 10.1038/s41522-025-00672-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 02/25/2025] [Indexed: 03/16/2025] Open
Abstract
Gut microbiota-derived metabolites play a crucial role in modulating the inflammatory response in inflammatory bowel disease (IBD). In this study, we identify gut microbiota-derived succinate as a driver of inflammation in ulcerative colitis (UC) by activating succinate-responsive, colitogenic helper T (Th) cells that secrete interleukin (IL)-9. We demonstrate that colitis is associated with an increase in succinate-producing gut bacteria and decrease in succinate-metabolizing gut bacteria. Similarly, UC patients exhibit elevated levels of succinate-producing gut bacteria and luminal succinate. Intestinal colonization by succinate-producing gut bacteria or increased succinate availability, exacerbates colonic inflammation by activating colitogenic Th9 cells. In contrast, intestinal colonization by succinate-metabolizing gut bacteria, blocking succinate receptor signaling with an antagonist, or neutralizing IL-9 with an anti-IL-9 antibody alleviates inflammation by reducing colitogenic Th9 cells. Our findings underscore the role of gut microbiota-derived succinate in driving colitogenic Th9 cells and suggesting its potential as a therapeutic target for treating IBD.
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Affiliation(s)
- Rajdeep Dalal
- Centre for Immunobiology and Immunotherapy, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3 rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
- Immunology Core Lab, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
- Jawaharlal Nehru University, New Delhi, India
| | - Srikanth Sadhu
- Centre for Immunobiology and Immunotherapy, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3 rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
- Immunology Core Lab, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
| | - Aashima Batra
- Department of Chemistry and Centre for Advanced Studies in Chemistry, Panjab University, Chandigarh, 160014, India
| | - Sandeep Goswami
- Centre for Immunobiology and Immunotherapy, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3 rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
- Immunology Core Lab, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
| | - Jyotsna Dandotiya
- Centre for Immunobiology and Immunotherapy, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3 rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
- Immunology Core Lab, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
| | - Vinayakadas K V
- Centre for Immunobiology and Immunotherapy, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3 rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
- Immunology Core Lab, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
| | - Rahul Yadav
- Centre for Immunobiology and Immunotherapy, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3 rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
- Immunology Core Lab, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
| | - Virendra Singh
- Centre for Immunobiology and Immunotherapy, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3 rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
- Immunology Core Lab, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
| | - Kartikey Chaturvedi
- Non-communicable disease centre, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
| | - Rahul Kannan
- Non-communicable disease centre, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
| | - Shakti Kumar
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, Uttar Pradesh, India
| | - Yashwant Kumar
- Non-communicable disease centre, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
| | - Deepak Kumar Rathore
- Centre for Immunobiology and Immunotherapy, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3 rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
- Immunology Core Lab, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India
| | - Deepak B Salunke
- Department of Chemistry and Centre for Advanced Studies in Chemistry, Panjab University, Chandigarh, 160014, India
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Mohali, 160062, Punjab, India
| | - Vineet Ahuja
- Department of Gastroenterology, All India Institute of Medical Sciences, Ansari Nagar East, New Delhi, India
| | - Amit Awasthi
- Centre for Immunobiology and Immunotherapy, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3 rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India.
- Immunology Core Lab, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India.
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Seo SM, Kim NW, Yoo ES, Lee JH, Kang AR, Jeong HB, Shim WY, Kim DH, Park YJ, Bae K, Yoon KA, Choi YK. Development of a novel complex inflammatory bowel disease mouse model: Reproducing human inflammatory bowel disease etiologies in mice. PLoS One 2024; 19:e0311310. [PMID: 39570897 PMCID: PMC11581264 DOI: 10.1371/journal.pone.0311310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 08/30/2024] [Indexed: 11/24/2024] Open
Abstract
Inflammatory bowel disease (IBD), caused by environmental factors associated with the host's genetic traits, is represented by Crohn's disease and ulcerative colitis. Despite the increasing number of patients with IBD, the current treatment is limited to symptomatic therapy. A complex IBD model mimicking the human IBD etiology is required to overcome this limitation. Herein, we developed novel complex IBD models using interleukin 2 receptor subunit gamma (Il2rg)-deficient mice, high-fat diet, dextran sodium sulfate, and Citrobacter rodentium. The more IBD factors applied complexly, colon length shortened and inflammation worsened. The levels of pro-inflammatory cytokines increased with increased IBD factors. Anti-inflammatory cytokine decreased in all factors application but increased in Il2rg deficiency and Westernized diet combination. Additionally, the pro-inflammatory transcription factors and leaky intestinal epithelial marker were upregulated by a combination of IBD factors. Species diversity decreased with IBD factors. Phylogenetic diversity decreased as IBD factors were applied but increased with combined Il2rg deficiency and Westernized diet. The more IBD factors applied complexly, the more severe the dysbiosis. Finally, we developed a novel complex IBD model using various IBD factors. This model more closely mimic human IBD based on colonic inflammation and dysbiosis than the previous models. Based on these results, our novel complex IBD model could be a valuable tool for further IBD research.
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Affiliation(s)
- Sun-Min Seo
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Na-Won Kim
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Eun-Seon Yoo
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Ji-Hun Lee
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Ah-Reum Kang
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Han-Bi Jeong
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Won-Yong Shim
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Dong-Hyun Kim
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Young-Jun Park
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Kieun Bae
- Department of Veterinary Biochemistry, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Kyong-Ah Yoon
- Department of Veterinary Biochemistry, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Yang-Kyu Choi
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
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5
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Shen W, Liang Y, Lv D, Xie N. Novel insights into the heterogeneity of FOXP3 + Treg cells in drug-induced allergic reactions through single-cell transcriptomics. Immunol Res 2024; 72:1071-1085. [PMID: 39073709 DOI: 10.1007/s12026-024-09509-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 06/16/2024] [Indexed: 07/30/2024]
Abstract
This study uncovers the novel heterogeneity of FOXP3 + regulatory T (Treg) cells and their pivotal role in modulating immune responses during drug-induced allergic reactions, employing cutting-edge single-cell transcriptomics. We established a mouse model for drug-induced allergic reactions and utilized single-cell RNA sequencing (scRNA-seq) to analyze the transcriptomic landscapes of FOXP3 + Treg cells isolated from affected tissues. The study involved both in vitro and in vivo approaches to evaluate the impact of FOXP3 expression levels on the immunoregulatory functions of Treg cells during allergic responses. Techniques included flow cytometry, cluster analysis, principal component analysis (PCA), CCK8 and CSFE assays for cell proliferation, LDH release assays for toxicity, ELISA for cytokine profiling, and CRISPR/Cas9 technology for gene editing. Our findings revealed significant transcriptomic heterogeneity among FOXP3 + Treg cells in the context of drug-induced allergic reactions, with distinct subpopulations exhibiting unique gene expression profiles. This heterogeneity suggests specialized roles in immune regulation. We observed a decrease in the proliferative capacity and cytokine secretion of FOXP3 + Treg cells following allergic stimulation, alongside an increase in reaction toxicity. Manipulating FOXP3 expression levels directly influenced these outcomes, where FOXP3 deletion exacerbated allergic responses, whereas its overexpression mitigated them. Notably, in vivo experiments demonstrated that FOXP3 overexpression significantly reduced the severity of allergic skin reactions in mice. Our study presents novel insights into the heterogeneity and crucial immunoregulatory role of FOXP3 + Treg cells during drug-induced allergic reactions. Overexpression of FOXP3 emerges as a potential therapeutic strategy to alleviate such allergic responses. These findings contribute significantly to our understanding of immune regulation and the development of targeted treatments for drug-induced allergies.
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Affiliation(s)
- Wei Shen
- Gansu Institute for Drug Control, No.7 Yin'an Road, Anning District, Lanzhou, 730000, Gansu Province, China
| | - Yibo Liang
- Gansu Institute for Drug Control, No.7 Yin'an Road, Anning District, Lanzhou, 730000, Gansu Province, China
| | - Dong Lv
- Gansu Institute for Drug Control, No.7 Yin'an Road, Anning District, Lanzhou, 730000, Gansu Province, China
| | - Nan Xie
- Gansu Institute for Drug Control, No.7 Yin'an Road, Anning District, Lanzhou, 730000, Gansu Province, China.
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6
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Honap S, Jairath V, Danese S, Peyrin-Biroulet L. Navigating the complexities of drug development for inflammatory bowel disease. Nat Rev Drug Discov 2024; 23:546-562. [PMID: 38778181 DOI: 10.1038/s41573-024-00953-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2024] [Indexed: 05/25/2024]
Abstract
Inflammatory bowel disease (IBD) - consisting of ulcerative colitis and Crohn's disease - is a complex, heterogeneous, immune-mediated inflammatory condition with a multifactorial aetiopathogenesis. Despite therapeutic advances in this arena, a ceiling effect has been reached with both single-agent monoclonal antibodies and advanced small molecules. Therefore, there is a need to identify novel targets, and the development of companion biomarkers to select responders is vital. In this Perspective, we examine how advances in machine learning and tissue engineering could be used at the preclinical stage where attrition rates are high. For novel agents reaching clinical trials, we explore factors decelerating progression, particularly the decline in IBD trial recruitment, and assess how innovative approaches such as reconfiguring trial designs, harmonizing end points and incorporating digital technologies into clinical trials can address this. Harnessing opportunities at each stage of the drug development process may allow for incremental gains towards more effective therapies.
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Affiliation(s)
- Sailish Honap
- Department of Gastroenterology, St George's University Hospitals NHS Foundation Trust, London, UK.
- School of Immunology and Microbial Sciences, King's College London, London, UK.
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France.
| | - Vipul Jairath
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University, London, Ontario, Canada
- Lawson Health Research Institute, Western University, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
| | - Silvio Danese
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Laurent Peyrin-Biroulet
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France.
- Department of Gastroenterology, Nancy University Hospital, Vandœuvre-lès-Nancy, France.
- INSERM, NGERE, University of Lorraine, Nancy, France.
- FHU-CURE, Nancy University Hospital, Vandœuvre-lès-Nancy, France.
- Groupe Hospitalier privé Ambroise Paré - Hartmann, Paris IBD Center, Neuilly sur Seine, France.
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada.
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Xin S, Liu X, He C, Gao H, Wang B, Hua R, Gao L, Shang H, Sun F, Xu J. Inflammation accelerating intestinal fibrosis: from mechanism to clinic. Eur J Med Res 2024; 29:335. [PMID: 38890719 PMCID: PMC11184829 DOI: 10.1186/s40001-024-01932-2] [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: 02/21/2024] [Accepted: 06/08/2024] [Indexed: 06/20/2024] Open
Abstract
Intestinal fibrosis is a prevalent complication of IBD that that can frequently be triggered by prolonged inflammation. Fibrosis in the gut can cause a number of issues, which continue as an ongoing challenge to healthcare systems worldwide. The primary causes of intestinal fibrosis are soluble molecules, G protein-coupled receptors, epithelial-to-mesenchymal or endothelial-to-mesenchymal transition, and the gut microbiota. Fresh perspectives coming from in vivo and in vitro experimental models demonstrate that fibrogenic pathways might be different, at least to some extent, independent of the ones that influence inflammation. Understanding the distinctive procedures of intestinal fibrogenesis should provide a realistic foundation for targeting and blocking specific fibrogenic pathways, estimating the risk of fibrotic consequences, detecting early fibrotic alterations, and eventually allowing therapy development. Here, we first summarize the inflammatory and non-inflammatory components of fibrosis, and then we elaborate on the underlying mechanism associated with multiple cytokines in fibrosis, providing the framework for future clinical practice. Following that, we discuss the relationship between modernization and disease, as well as the shortcomings of current studies. We outline fibrosis diagnosis and therapy, as well as our recommendations for the future treatment of intestinal fibrosis. We anticipate that the global review will provides a wealth of fresh knowledge and suggestions for future fibrosis clinical practice.
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Affiliation(s)
- Shuzi Xin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Xiaohui Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Chengwei He
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Han Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
- Department of Clinical Laboratory, Aerospace Clinical Medical College, Aerospace Central Hospital, Beijing, 100039, China
| | - Boya Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Rongxuan Hua
- Department of Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Lei Gao
- Department of Intelligent Medical Engineering, School of Biomedical Engineering, Capital Medical University, Beijing, 100069, China
| | - Hongwei Shang
- Experimental Center for Morphological Research Platform, Capital Medical University, Beijing, 100069, China
| | - Fangling Sun
- Department of Laboratory Animal Research, Xuan Wu Hospital, Capital Medical University, Beijing, 100053, China.
| | - Jingdong Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
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8
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Awad MM, El-Gohary RM, Ibrahim S, Abdel Ghafar MT, Farghal EE, Aboalsoud A, El-Shaer RAA. Potential mitigating impact of a dipeptidyl peptidase-IV inhibitor, vildagliptin, on oxazolone-induced ulcerative colitis: Targeting the role of PI3K/AKT/mTOR and AMPK/Nrf2 signaling pathways. Int Immunopharmacol 2024; 133:112110. [PMID: 38652960 DOI: 10.1016/j.intimp.2024.112110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 03/28/2024] [Accepted: 04/16/2024] [Indexed: 04/25/2024]
Abstract
Growing evidence suggests that phosphoinositide 3-kinase (PI3K) and adenosine monophosphate-activated protein kinase (AMPK) signaling cascades are critical in ulcerative colitis (UC) pathophysiology by influencing gut mucosal inflammation. Recently, the coloprotective properties of dipeptidyl peptidase-IV (DPP-IV) inhibitors have emerged. Thus, this study assessed for the first time the potential mitigating impact of a DPP-IV inhibitor, vildagliptin (Vilda), on oxazolone (OXZ)-induced colitis in rats, targeting the role of PI3K/AKT/mTOR and AMPK/Nrf2 pathways. Thirty-two adult Albino rats were divided into four groups: control, Vilda (10 mg/kg/day orally), OXZ (300 µL of 5 % OXZ in 50 % aqueous ethanol solution introduced once into the colon via catheter), and Vilda+OXZ. Inflammatory cytokines (interleukin 13, tumor necrosis factor-α, interleukin 10), oxidative/endoplasmic reticulum stress markers (myeloperoxidase, reduced glutathione, catalase, CHOP), mitochondrial reactive oxygen species, adenosine triphosphate levels, and mitochondrial transmembrane potential were estimated. p-AMPK, p-AKT, beclin-1, and SQSTM1 levels were immunoassayed. Nrf2, PI3K, and mTOR expression levels were quantified using the real-time polymerase chain reaction. Furthermore, p-NF-ĸBp65 and LC3II immunoreactivity were evaluated. Vilda administration effectively ameliorated OXZ-induced colitis, as evidenced by the reduced Disease Activity Index, macroscopic colon damage score, colon weight/length ratio, ulcer index, and histopathological and electron microscopic changes in the colon tissues. Vilda treatment also counteracted OXZ-triggered inflammation, oxidative/endoplasmic reticulum stress, mitochondrial dysfunction, and enhanced autophagy in the colon. Vilda substantially suppressed PI3K/AKT/mTOR and activated the AMPK/Nrf2 pathway. Vilda has potent coloprotective and anti-ulcerogenic properties, primarily attributed to its antiinflammatory, antioxidant, and modulatory impact on mitochondrial dysfunction and autophagy activity. These effects were mostly mediated by suppressing PI3K/AKT/mTOR and activating AMPK/Nrf2 signaling cascades, suggesting a potential role of Vilda in UC therapy.
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Affiliation(s)
- Marwa Mahmoud Awad
- Physiology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
| | - Rehab M El-Gohary
- Medical Biochemistry Department, Faculty of Medicine,Tanta University,Tanta, Egypt.
| | - Sarah Ibrahim
- Human Anatomy and Embryology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
| | | | - Eman E Farghal
- Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
| | - Alshimaa Aboalsoud
- Pharmacology Depatrtment, Faculty of Medicine, Tanta University, Tanta, Egypt.
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9
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Rieder F, Mukherjee PK, Massey WJ, Wang Y, Fiocchi C. Fibrosis in IBD: from pathogenesis to therapeutic targets. Gut 2024; 73:854-866. [PMID: 38233198 PMCID: PMC10997492 DOI: 10.1136/gutjnl-2023-329963] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 12/29/2023] [Indexed: 01/19/2024]
Abstract
BACKGROUND Intestinal fibrosis resulting in stricture formation and obstruction in Crohn's disease (CD) and increased wall stiffness leading to symptoms in ulcerative colitis (UC) is among the largest unmet needs in inflammatory bowel disease (IBD). Fibrosis is caused by a multifactorial and complex process involving immune and non-immune cells, their soluble mediators and exposure to luminal contents, such as microbiota and environmental factors. To date, no antifibrotic therapy is available. Some progress has been made in creating consensus definitions and measurements to quantify stricture morphology for clinical practice and trials, but approaches to determine the degree of fibrosis within a stricture are still lacking. OBJECTIVE We herein describe the current state of stricture pathogenesis, measuring tools and clinical trial endpoints development. DESIGN Data presented and discussed in this review derive from the past and recent literature and the authors' own research and experience. RESULTS AND CONCLUSIONS Significant progress has been made in better understanding the pathogenesis of fibrosis, but additional studies and preclinical developments are needed to define specific therapeutic targets.
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Affiliation(s)
- Florian Rieder
- Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Pranab K Mukherjee
- Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - William J Massey
- Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Yan Wang
- Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Claudio Fiocchi
- Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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10
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Abdel-Razek EAN, Mahmoud HM, Azouz AA. Management of ulcerative colitis by dichloroacetate: Impact on NFATC1/NLRP3/IL1B signaling based on bioinformatics analysis combined with in vivo experimental verification. Inflammopharmacology 2024; 32:667-682. [PMID: 37902927 PMCID: PMC10907436 DOI: 10.1007/s10787-023-01362-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 09/29/2023] [Indexed: 11/01/2023]
Abstract
The inflammatory response in ulcerative colitis (UC) could be relieved by the conventional immunomodulatory agents; 5-aminosalicylic acid, corticosteroids, or azathioprine. However, the low remission rates and the intolerance to these agents necessitate investigation of gene expression signature in UC that could influence the therapeutic efficacy of drugs, as well as the interference with persistence genes by novel therapeutic option. Three microarray datasets (GSE66407, GSE38713 and GSE14580) from the NCBI-GEO database were utilized. Differentially expressed genes between samples of patients with UC and healthy ones were analyzed using R software. In addition, in vivo study using oxazolone-induced UC in BALB/c mice was carried out to investigate the proposed therapeutic efficacy of dichloroacetate (DCA). The bioinformatics analysis revealed the persistence of NLRP3, NFATC1, and IL1B in UC despite treatment with common therapeutic agents. DCA administration to oxazolone-treated mice showed remarkable interference with those persistence genes. Western blotting analysis for NLRP3, NFATC1, nuclear/total NF-κB, and cleaved caspase-1 revealed the ability of DCA to reduce the expression levels of these proteins in oxazolone-treated mice. Additionally, the inflammatory cytokines IL-1β and IL-13 were reduced in colonic tissue by DCA treatment. The therapeutic efficacy of DCA was further confirmed by the apparent reduction in histopathological scoring, disease activity index, and the normalization of colon length. Therefore, DCA could be suggested as a novel and promising therapeutic option in UC based on its ability to interfere with the persistence of NFATC1/NLRP3/IL1B signaling. That merits further safety/toxicological pre-clinical assessment and update of bioavailability/metabolism data prior to clinical investigation.
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Affiliation(s)
| | - Heba M Mahmoud
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt
| | - Amany A Azouz
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt
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11
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Dsilva A, Avlas S, Rhone N, Itan M, Munitz A. A Mouse Model for Eosinophilic Esophagitis (EoE). Curr Protoc 2024; 4:e993. [PMID: 38372429 DOI: 10.1002/cpz1.993] [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] [Indexed: 02/20/2024]
Abstract
Eosinophilic esophagitis (EoE) is an emerging chronic T helper type 2 (Th2)-associated, allergic, and immune-mediated disease, characterized histologically by eosinophil-predominant mucosal inflammation and clinically by esophageal dysfunction. Over the past years, the prevalence of EoE has dramatically increased globally. Until recently, most studies of EoE focused on using human biopsies, which are also used for diagnostic purposes, or esophageal epithelial cell lines, which led to major advances in the understanding of EoE. Despite this, a robust mouse model that mimics human disease is still crucial for both understanding disease pathogenesis and as a preclinical model for testing future therapeutics. Herein, we describe a highly reproducible and robust model of EoE that can be performed using wild-type mice by ear sensitization with oxazolone (OXA) followed by intraesophageal challenges. Experimental EoE elicited by OXA mimics the main histopathological features of human EoE, including intraepithelial eosinophilia, epithelial and lamina propria thickening, basal cell hyperplasia, and fibrosis. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Induction of EoE in mice using oxazolone Support Protocol 1: Preparing the mouse esophagus for histological analysis Support Protocol 2: Assessment of epithelial and lamina propria thickness using H&E staining Support Protocol 3: Assessment of eosinophilic infiltration using anti-MBP and basal cell proliferation using anti-Ki-67 staining Support Protocol 4: Flow cytometry of mouse esophageal samples Support Protocol 5: ELISA on protein lysates of esophageal samples.
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Affiliation(s)
- Anish Dsilva
- Department of Clinical Microbiology and Immunology, Tel Aviv University, Israel
| | - Shmulik Avlas
- Department of Clinical Microbiology and Immunology, Tel Aviv University, Israel
| | - Natalie Rhone
- Department of Clinical Microbiology and Immunology, Tel Aviv University, Israel
| | - Michal Itan
- Department of Clinical Microbiology and Immunology, Tel Aviv University, Israel
| | - Ariel Munitz
- Department of Clinical Microbiology and Immunology, Tel Aviv University, Israel
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12
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Venken K, Decruy T, Sparwasser T, Elewaut D. Tregs protect against invariant NKT cell-mediated autoimmune colitis and hepatitis. Immunology 2024; 171:277-285. [PMID: 37984469 DOI: 10.1111/imm.13718] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 11/07/2023] [Indexed: 11/22/2023] Open
Abstract
Immunomodulatory T cells play a pivotal role in protection against (auto)immune-mediated diseases that open perspectives for therapeutic modulation. However, how immune regulatory networks operate in vivo is less understood. To this end, we focused on FOXP3+CD4+CD25+ regulatory T cells (Tregs) and invariant natural killer T (iNKT) cells, two lymphocyte populations that independently regulate adaptive and innate immune responses. In vitro, a functional interplay between Tregs and iNKT cells has been described, but whether Tregs modulate the function and phenotype of iNKT cell subsets in vivo and whether this controls iNKT-mediated autoimmunity is unclear. Taking advantage of the conditional depletion of Tregs, we examined the in vivo interplay between iNKT and Treg cells in steady state and in preclinical models of liver and gut autoimmunity. Under non-inflamed conditions, Treg depletion enhanced glycolipid-mediated iNKT cell responses, with a general impact on Type 1, 2 and 17 iNKT subsets. Moreover, in vivo iNKT activation in the absence of Tregs suppressed the induction of iNKT anergy, consistent with a reduction in programmed cell death receptor 1 (PD-1) expression. Importantly, we unveiled a clear role for an in vivo Treg-iNKT crosstalk both in concanavalin A-induced acute hepatitis and oxazolone-induced colitis. Here, the absence of Tregs led to a markedly enhanced liver and gut pathology, which was not observed in iNKT-deficient mice. Taken together, these results provide evidence for a functional interplay between regulatory T cell subsets critical in controlling the onset of autoimmune disease.
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Affiliation(s)
- Koen Venken
- Molecular Immunology and Inflammation Unit, VIB Center for Inflammation Research, Ghent University, Ghent, Belgium
- Faculty of Medicine and Health Sciences, Department of Internal Medicine and Pediatrics (Rheumatology unit), Ghent University, Ghent, Belgium
| | - Tine Decruy
- Molecular Immunology and Inflammation Unit, VIB Center for Inflammation Research, Ghent University, Ghent, Belgium
- Faculty of Medicine and Health Sciences, Department of Internal Medicine and Pediatrics (Rheumatology unit), Ghent University, Ghent, Belgium
| | - Tim Sparwasser
- Department of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Dirk Elewaut
- Molecular Immunology and Inflammation Unit, VIB Center for Inflammation Research, Ghent University, Ghent, Belgium
- Faculty of Medicine and Health Sciences, Department of Internal Medicine and Pediatrics (Rheumatology unit), Ghent University, Ghent, Belgium
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13
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Karmele EP, Moldoveanu AL, Kaymak I, Jugder BE, Ursin RL, Bednar KJ, Corridoni D, Ort T. Single cell RNA-sequencing profiling to improve the translation between human IBD and in vivo models. Front Immunol 2023; 14:1291990. [PMID: 38179052 PMCID: PMC10766350 DOI: 10.3389/fimmu.2023.1291990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 11/29/2023] [Indexed: 01/06/2024] Open
Abstract
Inflammatory bowel disease (IBD) is an umbrella term for two conditions (Crohn's Disease and Ulcerative Colitis) that is characterized by chronic inflammation of the gastrointestinal tract. The use of pre-clinical animal models has been invaluable for the understanding of potential disease mechanisms. However, despite promising results of numerous therapeutics in mouse colitis models, many of these therapies did not show clinical benefits in patients with IBD. Single cell RNA-sequencing (scRNA-seq) has recently revolutionized our understanding of complex interactions between the immune system, stromal cells, and epithelial cells by mapping novel cell subpopulations and their remodeling during disease. This technology has not been widely applied to pre-clinical models of IBD. ScRNA-seq profiling of murine models may provide an opportunity to increase the translatability into the clinic, and to choose the most appropriate model to test hypotheses and novel therapeutics. In this review, we have summarized some of the key findings at the single cell transcriptomic level in IBD, how specific signatures have been functionally validated in vivo, and highlighted the similarities and differences between scRNA-seq findings in human IBD and experimental mouse models. In each section of this review, we highlight the importance of utilizing this technology to find the most suitable or translational models of IBD based on the cellular therapeutic target.
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Affiliation(s)
- Erik P. Karmele
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
| | - Ana Laura Moldoveanu
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Irem Kaymak
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Bat-Erdene Jugder
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Waltham, MA, United States
| | - Rebecca L. Ursin
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Waltham, MA, United States
| | - Kyle J. Bednar
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
| | - Daniele Corridoni
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Tatiana Ort
- Bioscience Immunology, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United States
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14
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Xia Y, Liu C, Li R, Zheng M, Feng B, Gao J, Long X, Li L, Li S, Zuo X, Li Y. Lactobacillus-derived indole-3-lactic acid ameliorates colitis in cesarean-born offspring via activation of aryl hydrocarbon receptor. iScience 2023; 26:108279. [PMID: 38026194 PMCID: PMC10656274 DOI: 10.1016/j.isci.2023.108279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/09/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023] Open
Abstract
Cesarean section (CS) delivery is known to disrupt the transmission of maternal microbiota to offspring, leading to an increased risk of inflammatory bowel disease (IBD). However, the underlying mechanisms remain poorly characterized. Here, we demonstrate that CS birth renders mice susceptible to dextran sulfate sodium (DSS)-induced colitis and impairs group 3 innate lymphoid cell (ILC3) development. Additionally, CS induces a sustained decrease in Lactobacillus abundance, which subsequently contributes to the colitis progression and ILC3 deficiency. Supplementation with a probiotic strain, L. acidophilus, or its metabolite, indole-3-lactic acid (ILA), can attenuate intestinal inflammation and restore ILC3 frequency and interleukin (IL)-22 level in CS offspring. Mechanistically, we indicate that ILA activates ILC3 through the aryl hydrocarbon receptor (AhR) signaling. Overall, our findings uncover a detrimental role of CS-induced gut dysbiosis in the pathogenesis of colitis and suggest L. acidophilus and ILA as potential targets to re-establish intestinal homeostasis in CS offspring.
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Affiliation(s)
- Yanan Xia
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Chang Liu
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Ruijia Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Mengqi Zheng
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Bingcheng Feng
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Jiahui Gao
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Xin Long
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Lixiang Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Shandong Provincial Clinical Research Center for Digestive Disease, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Shiyang Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Advanced Medical Research Institute, Shandong University, Jinan, China
| | - Xiuli Zuo
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Shandong Provincial Clinical Research Center for Digestive Disease, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yanqing Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
- Shandong Provincial Clinical Research Center for Digestive Disease, Qilu Hospital of Shandong University, Jinan, Shandong, China
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15
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Kelly C, Jawahar J, Davey L, Everitt JI, Galanko JA, Anderson C, Avendano JE, McCann JR, Sartor RB, Valdivia RH, Rawls JF. Spontaneous episodic inflammation in the intestines of mice lacking HNF4A is driven by microbiota and associated with early life microbiota alterations. mBio 2023; 14:e0150423. [PMID: 37526424 PMCID: PMC10470520 DOI: 10.1128/mbio.01504-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 06/22/2023] [Indexed: 08/02/2023] Open
Abstract
The inflammatory bowel diseases (IBD) occur in genetically susceptible individuals who mount inappropriate immune responses to their microbiota leading to chronic intestinal inflammation. Whereas IBD clinical presentation is well described, how interactions between microbiota and host genotype impact early subclinical stages of the disease remains unclear. The transcription factor hepatocyte nuclear factor 4 alpha (HNF4A) has been associated with human IBD, and deletion of Hnf4a in intestinal epithelial cells (IECs) in mice (Hnf4aΔIEC) leads to spontaneous colonic inflammation by 6-12 mo of age. Here, we tested if pathology in Hnf4aΔIEC mice begins earlier in life and if microbiota contribute to that process. Longitudinal analysis revealed that Hnf4aΔIEC mice reared in specific pathogen-free (SPF) conditions develop episodic elevated fecal lipocalin 2 (Lcn2) and loose stools beginning by 4-5 wk of age. Lifetime cumulative Lcn2 levels correlated with histopathological features of colitis at 12 mo. Antibiotic and gnotobiotic tests showed that these phenotypes in Hnf4aΔIEC mice were dependent on microbiota. Fecal 16S rRNA gene sequencing in SPF Hnf4aΔIEC and control mice disclosed that genotype significantly contributed to differences in microbiota composition by 12 mo, and longitudinal analysis of the Hnf4aΔIEC mice with the highest lifetime cumulative Lcn2 revealed that microbial community differences emerged early in life when elevated fecal Lcn2 was first detected. These microbiota differences included enrichment of a novel phylogroup of Akkermansia muciniphila in Hnf4aΔIEC mice. We conclude that HNF4A functions in IEC to shape composition of the gut microbiota and protect against episodic inflammation induced by microbiota throughout the lifespan. IMPORTANCE The inflammatory bowel diseases (IBD), characterized by chronic inflammation of the intestine, affect millions of people around the world. Although significant advances have been made in the clinical management of IBD, the early subclinical stages of IBD are not well defined and are difficult to study in humans. This work explores the subclinical stages of disease in mice lacking the IBD-associated transcription factor HNF4A in the intestinal epithelium. Whereas these mice do not develop overt disease until late in adulthood, we find that they display episodic intestinal inflammation, loose stools, and microbiota changes beginning in very early life stages. Using germ-free and antibiotic-treatment experiments, we reveal that intestinal inflammation in these mice was dependent on the presence of microbiota. These results suggest that interactions between host genotype and microbiota can drive early subclinical pathologies that precede the overt onset of IBD and describe a mouse model to explore those important processes.
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Affiliation(s)
- Cecelia Kelly
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina, USA
| | - Jayanth Jawahar
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina, USA
| | - Lauren Davey
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina, USA
- Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA
| | - Jeffrey I. Everitt
- Department of Pathology, Research Animal Pathology Core, Duke University School of Medicine, Durham, North Carolina, USA
| | - Joseph A. Galanko
- Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Chelsea Anderson
- Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jonathan E. Avendano
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina, USA
| | - Jessica R. McCann
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina, USA
| | - R. Balfour Sartor
- Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Raphael H. Valdivia
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina, USA
- Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA
| | - John F. Rawls
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina, USA
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16
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Hu C, Liao S, Lv L, Li C, Mei Z. Intestinal Immune Imbalance is an Alarm in the Development of IBD. Mediators Inflamm 2023; 2023:1073984. [PMID: 37554552 PMCID: PMC10406561 DOI: 10.1155/2023/1073984] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/06/2023] [Accepted: 07/08/2023] [Indexed: 08/10/2023] Open
Abstract
Immune regulation plays a crucial role in human health and disease. Inflammatory bowel disease (IBD) is a chronic relapse bowel disease with an increasing incidence worldwide. Clinical treatments for IBD are limited and inefficient. However, the pathogenesis of immune-mediated IBD remains unclear. This review describes the activation of innate and adaptive immune functions by intestinal immune cells to regulate intestinal immune balance and maintain intestinal mucosal integrity. Changes in susceptible genes, autophagy, energy metabolism, and other factors interact in a complex manner with the immune system, eventually leading to intestinal immune imbalance and the onset of IBD. These events indicate that intestinal immune imbalance is an alarm for IBD development, further opening new possibilities for the unprecedented development of immunotherapy for IBD.
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Affiliation(s)
- Chunli Hu
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Shengtao Liao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Lin Lv
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Chuanfei Li
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Zhechuan Mei
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
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17
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Luo J, Chen Z, Castellano D, Bao B, Han W, Li J, Kim G, An D, Lu W, Wu C. Lipids regulate peripheral serotonin release via gut CD1d. Immunity 2023; 56:1533-1547.e7. [PMID: 37354904 PMCID: PMC10527042 DOI: 10.1016/j.immuni.2023.06.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 03/04/2023] [Accepted: 06/01/2023] [Indexed: 06/26/2023]
Abstract
The crosstalk between the immune and neuroendocrine systems is critical for intestinal homeostasis and gut-brain communications. However, it remains unclear how immune cells participate in gut sensation of hormones and neurotransmitters release in response to environmental cues, such as self-lipids and microbial lipids. We show here that lipid-mediated engagement of invariant natural killer T (iNKT) cells with enterochromaffin (EC) cells, a subset of intestinal epithelial cells, promoted peripheral serotonin (5-HT) release via a CD1d-dependent manner, regulating gut motility and hemostasis. We also demonstrated that inhibitory sphingolipids from symbiotic microbe Bacteroides fragilis represses 5-HT release. Mechanistically, CD1d ligation on EC cells transduced a signal and restrained potassium conductance through activation of protein tyrosine kinase Pyk2, leading to calcium influx and 5-HT secretion. Together, our data reveal that by engaging with iNKT cells, gut chemosensory cells selectively perceive lipid antigens via CD1d to control 5-HT release, modulating intestinal and systemic homeostasis.
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Affiliation(s)
- Jialie Luo
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Zuojia Chen
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD, USA
| | - David Castellano
- Synapse and Neural Circuit Research Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
| | - Bin Bao
- Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Wenyan Han
- Synapse and Neural Circuit Research Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
| | - Jian Li
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Girak Kim
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Dingding An
- Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Wei Lu
- Synapse and Neural Circuit Research Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
| | - Chuan Wu
- Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
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18
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Lam GA, Albarrak H, McColl CJ, Pizarro A, Sanaka H, Gomez-Nguyen A, Cominelli F, Paes Batista da Silva A. The Oral-Gut Axis: Periodontal Diseases and Gastrointestinal Disorders. Inflamm Bowel Dis 2023; 29:1153-1164. [PMID: 36527679 PMCID: PMC10320234 DOI: 10.1093/ibd/izac241] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Indexed: 06/17/2023]
Abstract
One of the prospective sequelae of periodontal disease (PD), chronic inflammation of the oral mucosa, is the development of inflammatory gastrointestinal (GI) disorders due to the amplification and expansion of the oral pathobionts. In addition, chronic inflammatory diseases related to the GI tract, which include inflammatory bowel disease (IBD), can lead to malignancy susceptibility in the colon of both animals and humans. Recent studies suggest that dysbiosis of the oral microbiota can alter the microbial composition in relative abundance or diversity of the distal gut, leading to the progression of digestive carcinogenesis. The link between PD and specific GI disorders is also closely associated with the migration and colonization of periodontal pathogens and the subsequent microbe-reactive T cell induction within the intestines. In this review, an in-depth examination of this relationship and the accessibility of different mouse models of IBD and PD may shed light on the current dogma. As such, oral microbiota dysbiosis involving specific bacteria, including Fusobacterium nucleatum and Porphyromonas gingivalis, can ultimately lead to gut malignancies. Further understanding the precise mechanism(s) of the oral-gut microbial axis in PD, IBD, and colorectal cancer pathogenesis will be pivotal in diagnosis, prognosis, and future treatment.
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Affiliation(s)
- Gretchen A Lam
- Digestive Health Research Institute, Case Western Reserve University, Cleveland, OH, USA
- School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Hala Albarrak
- School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Periodontics, Case Western Reserve University, Cleveland, Ohio, USA
| | | | | | | | - Adrian Gomez-Nguyen
- Department of Medicine, Case Western Reserve University, Cleveland, OH, USA
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
| | - Fabio Cominelli
- Digestive Health Research Institute, Case Western Reserve University, Cleveland, OH, USA
- Department of Medicine, Case Western Reserve University, Cleveland, OH, USA
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
| | - Andre Paes Batista da Silva
- School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Periodontics, Case Western Reserve University, Cleveland, Ohio, USA
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19
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Chen SY, Chu CT, Yang ML, Lin JD, Wang CT, Lee CH, Lin IC, Shiau AL, Ling P, Wu CL. Amelioration of Murine Colitis by Attenuated Salmonella choleraesuis Encoding Interleukin-19. Microorganisms 2023; 11:1530. [PMID: 37375032 DOI: 10.3390/microorganisms11061530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/05/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
The imbalance of mucosal immunity in the lower gastrointestinal tract can lead to chronic inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis. IBD is a chronic inflammatory disorder that causes small and/or large intestines ulceration. According to previous studies, recombinant interleukin (IL)-10 protein and genetically modified bacteria secreting IL-10 ameliorate dextran sulfate sodium (DSS)-induced colitis in mice. IL-19 is a transcriptional activator of IL-10 and can alter the balance of T helper 1 (Th)1/Th2 cells in favor of Th2. In this study, we aimed to investigate whether the expression of the murine IL-19 gene carried by Salmonella choleraesuis (S. choleraesuis) could ameliorate murine IBD. Our results showed that the attenuated S. choleraesuis could carry and express the IL-19 gene-containing plasmid for IBD gene therapy by reducing the mortality and clinical signs in DSS-induced acute colitis mice as compared to the untreated ones. We also found that IL-10 expression was induced in IL-19-treated colitis mice and prevented inflammatory infiltrates and proinflammatory cytokine expression in these mice. We suggest that S. choleraesuis encoding IL-19 provides a new strategy for treating IBD in the future.
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Affiliation(s)
- Shih-Yao Chen
- Department of Nursing, College of Nursing, Chung Hwa University of Medical Technology, Tainan 71703, Taiwan
| | - Chun-Ting Chu
- Division of Colorectal Surgery, Department of Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, 539, Zhongxiao Road, Chiayi City 60002, Taiwan
| | - Mei-Lin Yang
- Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City 60002, Taiwan
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Jian-Da Lin
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
- Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei City 10617, Taiwan
| | - Chung-Teng Wang
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Che-Hsin Lee
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
| | - I-Chen Lin
- Division of Colorectal Surgery, Department of Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, 539, Zhongxiao Road, Chiayi City 60002, Taiwan
| | - Ai-Li Shiau
- Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City 60002, Taiwan
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Pin Ling
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Chao-Liang Wu
- Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City 60002, Taiwan
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
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20
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Viola MF, Chavero-Pieres M, Modave E, Delfini M, Stakenborg N, Estévez MC, Fabre N, Appeltans I, Martens T, Vandereyken K, Theobald H, Van Herck J, Petry P, Verheijden S, De Schepper S, Sifrim A, Liu Z, Ginhoux F, Azhar M, Schlitzer A, Matteoli G, Kierdorf K, Prinz M, Vanden Berghe P, Voet T, Boeckxstaens G. Dedicated macrophages organize and maintain the enteric nervous system. Nature 2023; 618:818-826. [PMID: 37316669 DOI: 10.1038/s41586-023-06200-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 05/11/2023] [Indexed: 06/16/2023]
Abstract
Correct development and maturation of the enteric nervous system (ENS) is critical for survival1. At birth, the ENS is immature and requires considerable refinement to exert its functions in adulthood2. Here we demonstrate that resident macrophages of the muscularis externa (MMϕ) refine the ENS early in life by pruning synapses and phagocytosing enteric neurons. Depletion of MMϕ before weaning disrupts this process and results in abnormal intestinal transit. After weaning, MMϕ continue to interact closely with the ENS and acquire a neurosupportive phenotype. The latter is instructed by transforming growth factor-β produced by the ENS; depletion of the ENS and disruption of transforming growth factor-β signalling result in a decrease in neuron-associated MMϕ associated with loss of enteric neurons and altered intestinal transit. These findings introduce a new reciprocal cell-cell communication responsible for maintenance of the ENS and indicate that the ENS, similarly to the brain, is shaped and maintained by a dedicated population of resident macrophages that adapts its phenotype and transcriptome to the timely needs of the ENS niche.
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Affiliation(s)
- Maria Francesca Viola
- Laboratory for Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Marta Chavero-Pieres
- Laboratory for Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Elodie Modave
- Laboratory for Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Marcello Delfini
- Laboratory for Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Nathalie Stakenborg
- Laboratory for Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Maria Cuende Estévez
- Laboratory for Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Naomi Fabre
- Laboratory for Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Iris Appeltans
- Laboratory for Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Tobie Martens
- Laboratory for Enteric NeuroScience, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Katy Vandereyken
- Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, Belgium
- KU Leuven Institute for Single Cell Omics, KU Leuven, Leuven, Belgium
| | - Hannah Theobald
- Quantitative Systems Biology, LIMES-Institute, University of Bonn, Bonn, Germany
| | - Jens Van Herck
- Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, Belgium
| | - Philippe Petry
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Simon Verheijden
- Laboratory for Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
- Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium
| | - Sebastiaan De Schepper
- Laboratory for Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
- UK Dementia Research Institute, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK
| | - Alejandro Sifrim
- KU Leuven Institute for Single Cell Omics, KU Leuven, Leuven, Belgium
- Laboratory of Multi-Omic Integrative Bioinformatics, Department of Genetics, KU Leuven, Leuven, Belgium
- Leuven AI Institute, KU Leuven, Leuven, Belgium
| | - Zhaoyuan Liu
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Florent Ginhoux
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Singapore Immunology Network, Agency for Science, Technology & Research, Singapore, Singapore
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
| | - Mohamad Azhar
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Andreas Schlitzer
- Quantitative Systems Biology, LIMES-Institute, University of Bonn, Bonn, Germany
| | - Gianluca Matteoli
- Laboratory for Mucosal Immunology, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Katrin Kierdorf
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
- Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Marco Prinz
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Pieter Vanden Berghe
- Laboratory for Enteric NeuroScience, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Thierry Voet
- Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, Belgium
- KU Leuven Institute for Single Cell Omics, KU Leuven, Leuven, Belgium
| | - Guy Boeckxstaens
- Laboratory for Intestinal Neuro-Immune Interaction, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
- KU Leuven Institute for Single Cell Omics, KU Leuven, Leuven, Belgium.
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21
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Shin AE, Tesfagiorgis Y, Larsen F, Derouet M, Zeng PYF, Good HJ, Zhang L, Rubinstein MR, Han YW, Kerfoot SM, Nichols AC, Hayakawa Y, Howlett CJ, Wang TC, Asfaha S. F4/80 +Ly6C high Macrophages Lead to Cell Plasticity and Cancer Initiation in Colitis. Gastroenterology 2023; 164:593-609.e13. [PMID: 36634827 PMCID: PMC10038892 DOI: 10.1053/j.gastro.2023.01.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 12/15/2022] [Accepted: 01/03/2023] [Indexed: 01/14/2023]
Abstract
BACKGROUND & AIMS Colorectal cancer is a leading cause of cancer death, and a major risk factor is chronic inflammation. Despite the link between colitis and cancer, the mechanism by which inflammation leads to colorectal cancer is not well understood. METHODS To investigate whether different forms of inflammation pose the same risk of cancer, we compared several murine models of colitis (dextran sodium sulfate [DSS], 2,4,6-trinitrobenzene sulfonic acid, 4-ethoxylmethylene-2-phenyloxazol-5-one, Citrobacter rodentium, Fusobacterium nucleatum, and doxorubicin) with respect to their ability to lead to colonic tumorigenesis. We attempted to correlate the severity of colitis and inflammatory profile with the risk of tumorigenesis in both azoxymethane-dependent and Dclk1/APCfl/fl murine models of colitis-associated cancer. RESULTS DSS colitis reproducibly led to colonic tumors in both mouse models of colitis-associated cancer. In contrast, all other forms of colitis did not lead to cancer. When compared with the colitis not associated with tumorigenesis, DSS colitis was characterized by significantly increased CD11b+F4/80+Ly6Chigh macrophages and CD11b+Ly6G+ neutrophils. Interestingly, depletion of the CD11b+F4/80+Ly6Chigh macrophages inhibited tumorigenesis, whereas depletion of CD11b+Ly6G+ neutrophils had no effect on tumorigenesis. Furthermore, the macrophage-derived cytokines interleukin-1β, tumor necrosis factor-α, and interleukin-6 were significantly increased in DSS colitis and promoted stemness of Dclk1+ tuft cells that serve as the cellular origin of cancer. CONCLUSIONS We have identified CD11b+F4/80+Ly6Chigh macrophages as key mediators of cancer initiation in colitis-associated cancer. Development of new therapies that target these cells may provide an effective preventative strategy for colitis-associated cancer.
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Affiliation(s)
- Alice E Shin
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada
| | - Yodit Tesfagiorgis
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - Frederikke Larsen
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada
| | - Mathieu Derouet
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada
| | - Peter Y F Zeng
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Otolaryngology and Head and Neck Surgery, Western University, London, Ontario, Canada
| | - Hayley J Good
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada
| | - Liyue Zhang
- Department of Medicine, Western University, London, Ontario, Canada
| | - Mara R Rubinstein
- Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University Irving Medical Center, New York, New York
| | - Yiping W Han
- Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University Irving Medical Center, New York, New York; Departments of Microbiology & Immunology and Medicine (Medical Sciences), Columbia University Irving Medical Center, New York, New York
| | - Steven M Kerfoot
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - Anthony C Nichols
- Department of Otolaryngology and Head and Neck Surgery, Western University, London, Ontario, Canada
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Christopher J Howlett
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Timothy C Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Samuel Asfaha
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada.
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22
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Moderating Gut Microbiome/Mitochondrial Axis in Oxazolone Induced Ulcerative Colitis: The Evolving Role of β-Glucan and/or, Aldose Reductase Inhibitor, Fidarestat. Int J Mol Sci 2023; 24:ijms24032711. [PMID: 36769034 PMCID: PMC9917140 DOI: 10.3390/ijms24032711] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/18/2023] [Accepted: 01/20/2023] [Indexed: 02/04/2023] Open
Abstract
A mechanistic understanding of the dynamic interactions between the mitochondria and the gut microbiome is thought to offer innovative explanations for many diseases and thus provide innovative management approaches, especially in GIT-related autoimmune diseases, such as ulcerative colitis (UC). β-Glucans, important components of many nutritious diets, including oats and mushrooms, have been shown to exhibit a variety of biological anti-inflammatory and immune-modulating actions. Our research study sought to provide insight into the function of β-glucan and/or fidarestat in modifying the microbiome/mitochondrial gut axis in the treatment of UC. A total of 50 Wistar albino male rats were grouped into five groups: control, UC, β-Glucan, Fidarestat, and combined treatment groups. All the groups were tested for the presence of free fatty acid receptors 2 and 3 (FFAR-2 and -3) and mitochondrial transcription factor A (TFAM) mRNA gene expressions. The reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP content were found. The trimethylamine N-oxide (TMAO) and short-chain fatty acid (SCFA) levels were also examined. Nuclear factor kappa β (NF-kβ), nuclear factor (erythroid-2)-related factor 2 (Nrf2) DNA binding activity, and peroxisome proliferator-activated receptor gamma co-activator-1 (PGC-1) were identified using the ELISA method. We observed a substantial increase FFAR-2, -3, and TFAM mRNA expression after the therapy. Similar increases were seen in the ATP levels, MMP, SCFA, PGC-1, and Nrf2 DNA binding activity. The levels of ROS, TMAO, and NF-kβ, on the other hand, significantly decreased. Using β-glucan and fidarestat together had unique therapeutic benefits in treating UC by focusing on the microbiota/mitochondrial axis, opening up a new avenue for a potential treatment for such a complex, multidimensional illness.
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23
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Gomez-Bris R, Saez A, Herrero-Fernandez B, Rius C, Sanchez-Martinez H, Gonzalez-Granado JM. CD4 T-Cell Subsets and the Pathophysiology of Inflammatory Bowel Disease. Int J Mol Sci 2023; 24:2696. [PMID: 36769019 PMCID: PMC9916759 DOI: 10.3390/ijms24032696] [Citation(s) in RCA: 91] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/24/2023] [Accepted: 01/28/2023] [Indexed: 02/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an umbrella term for the chronic immune-mediated idiopathic inflammation of the gastrointestinal tract, manifesting as Crohn's disease (CD) or ulcerative colitis (UC). IBD is characterized by exacerbated innate and adaptive immunity in the gut in association with microbiota dysbiosis and the disruption of the intestinal barrier, resulting in increased bacterial exposure. In response to signals from microorganisms and damaged tissue, innate immune cells produce inflammatory cytokines and factors that stimulate T and B cells of the adaptive immune system, and a prominent characteristic of IBD patients is the accumulation of inflammatory T-cells and their proinflammatory-associated cytokines in intestinal tissue. Upon antigen recognition and activation, CD4 T-cells differentiate towards a range of distinct phenotypes: T helper(h)1, Th2, Th9, Th17, Th22, T follicular helper (Tfh), and several types of T-regulatory cells (Treg). T-cells are generated according to and adapt to microenvironmental conditions and participate in a complex network of interactions among other immune cells that modulate the further progression of IBD. This review examines the role of the CD4 T-cells most relevant to IBD, highlighting how these cells adapt to the environment and interact with other cell populations to promote or inhibit the development of IBD.
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Affiliation(s)
- Raquel Gomez-Bris
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Angela Saez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria (UFV), 28223 Pozuelo de Alarcón, Spain
| | - Beatriz Herrero-Fernandez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Cristina Rius
- Department of History of Science and Information Science, School of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain
- UISYS Research Unit, University of Valencia, 46010 Valencia, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
| | - Hector Sanchez-Martinez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
| | - Jose M. Gonzalez-Granado
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
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24
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Secher T, Couturier A, Huot L, Bouscayrol H, Grandjean T, Boulard O, Hot D, Ryffel B, Chamaillard M. A Protective Role of NOD2 on Oxazolone-induced Intestinal Inflammation Through IL-1β-mediated Signalling Pathway. J Crohns Colitis 2023; 17:111-122. [PMID: 35917251 DOI: 10.1093/ecco-jcc/jjac106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND AND AIMS NOD2 has emerged as a critical player in the induction of both Th1 and Th2 responses for potentiation and polarisation of antigen-dependent immunity. Loss-of-function mutations in the NOD2-encoding gene and deregulation of its downstream signalling pathway have been linked to Crohn's disease. Although it is well documented that NOD2 is capable of sensing bacterial muramyl dipeptide, it remains counter-intuitive to link development of overt intestinal inflammation to a loss of bacterial-induced inflammatory response. We hypothesised that a T helper bias could also contribute to an autoimmune-like colitis different from inflammation that is fully fledged by Th1 type cells. METHODS An oedematous bowel wall with a mixed Th1/Th2 response was induced in mice by intrarectal instillation of the haptenating agent oxazolone. Survival and clinical scoring were evaluated. At several time points after instillation, colonic damage was assessed by macroscopic and microscopic observations. To evaluate the involvement of NOD2 in immunochemical phenomena, quantitative polymerase chain reaction [PCR] and flow cytometry analysis were performed. Bone marrow chimera experimentation allowed us to evaluate the role of haematopoietic/non-hematopoietic NOD2-expressing cells. RESULTS Herein, we identified a key regulatory circuit whereby NOD2-mediated sensing of a muramyl dipeptide [MDP] by radio-resistant cells improves colitis with a mixed Th1/Th2 response that is induced by oxazolone. Genetic ablation of either Nod2 or Ripk2 precipitated oxazolone colitis that is predominantly linked to a lack of interferon-gamma. Bone marrow chimera experiments revealed that inactivation of Nod2 signalling in non-haematopoietic cells is causing a biased M1-M2 polarisation of macrophages and a decreased frequency of splenic regulatory T cells that correlates with an impaired activation of CD4 + T cells within mesenteric lymph nodes. Mechanistically, mice were protected from oxazolone-induced colitis upon administration of MDP in an interleukin-1- and interleukin-23-dependent manner. CONCLUSIONS These findings indicate that Nod2 signalling may prevent pathological conversion of T helper cells for maintenance of tissue homeostasis.
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Affiliation(s)
- Thomas Secher
- INEM, Orléans University, CNRS UMR 7355, F-45071, Orléans, France.,CEPR, Tours University, INSERM U1100, F-37000, Tours, France
| | | | - Ludovic Huot
- Centre d'Infection et d'Immunité de Lille, Université de Lille, CNRS, Inserm, CHRU Lille, Institut Pasteur de Lille, U1019-UMR 9017, F-59000, Lille, France
| | - Helene Bouscayrol
- Service d'oncologie-radiothérapie, CHR d'Orléans-La Source, Orléans, France
| | - Teddy Grandjean
- Centre d'Infection et d'Immunité de Lille, Université de Lille, CNRS, Inserm, CHRU Lille, Institut Pasteur de Lille, U1019-UMR 9017, F-59000, Lille, France
| | - Olivier Boulard
- Laboratory of Cell Physiology, Inserm U1003, University of Lille, Lille, France
| | - David Hot
- CEPR, Tours University, INSERM U1100, F-37000, Tours, France.,University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41-UAR 2014-PLBS, F-59000 Lille, France
| | - Bernhard Ryffel
- INEM, Orléans University, CNRS UMR 7355, F-45071, Orléans, France
| | - Mathias Chamaillard
- Laboratory of Cell Physiology, Inserm U1003, University of Lille, Lille, France
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25
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Monteleone G, Laudisi F, Stolfi C. Smad7 as a positive regulator of intestinal inflammatory diseases. CURRENT RESEARCH IN IMMUNOLOGY 2023; 4:100055. [PMID: 36714553 PMCID: PMC9881044 DOI: 10.1016/j.crimmu.2023.100055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/12/2023] [Accepted: 01/18/2023] [Indexed: 01/26/2023] Open
Abstract
In physiological conditions, the human gut contains more immune cells than the rest of the body, but no overt tissue damage occurs, because several regulatory mechanisms control the activity of such cells thus preventing excessive and detrimental responses. One such mechanism relies on the action of transforming growth factor (TGF)-β1, a cytokine that targets both epithelial cells and many immune cell types. Loss of TGF-β1 function leads to intestinal pathology in both mice and humans. For instance, disruption of TGF-β1 signaling characterizes the destructive immune-inflammatory response in patients with Crohn's disease and patients with ulcerative colitis, the major human inflammatory bowel disease (IBD) entities. In these pathologies, the defective TGF-β1-mediated anti-inflammatory response is associated with elevated intestinal levels of Smad7, an antagonist of TGF-β1 signaling. Consistently, knockdown of Smad7 restores TGF-β1 function thereby attenuating intestinal inflammation in patients with IBD as well as in mice with IBD-like colitis. Up-regulation of Smad7 and reduced TGF-β1 signaling occurs also in necrotizing enterocolitis, environmental enteropathy, refractory celiac disease, and cytomegalovirus-induced colitis. In this article, we review the available data supporting the pathogenic role of Smad7 in the gastrointestinal tract and discuss whether and how targeting Smad7 can help attenuate detrimental immuno-inflammatory responses in the gut.
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Affiliation(s)
- Giovanni Monteleone
- Corresponding author. Dipartimento di Medicina dei Sistemi, Università di Roma “Tor Vergata”, Via Montpellier 1, 00133, Rome, Italy.
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26
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Sakamoto E, Katahira Y, Mizoguchi I, Watanabe A, Furusaka Y, Sekine A, Yamagishi M, Sonoda J, Miyakawa S, Inoue S, Hasegawa H, Yo K, Yamaji F, Toyoda A, Yoshimoto T. Chemical- and Drug-Induced Allergic, Inflammatory, and Autoimmune Diseases Via Haptenation. BIOLOGY 2023; 12:biology12010123. [PMID: 36671815 PMCID: PMC9855847 DOI: 10.3390/biology12010123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/23/2022] [Accepted: 01/10/2023] [Indexed: 01/15/2023]
Abstract
Haptens are small molecules that only elicit an immune response when bound to proteins. Haptens initially bind to self-proteins and activate innate immune responses by complex mechanisms via inflammatory cytokines and damage-associated molecular patterns and the subsequent upregulation of costimulatory signals such as cluster of differentiation 86 (CD86) on dendritic cells. Subsequent interactions between CD86 and CD28 on T cells are critically important for properly activating naive T cells and inducing interleukin 2 production, leading to the establishment of adaptive immunity via effector and memory T cells. Accumulating evidence revealed the involvement of haptens in the development of various autoimmune-like diseases such as allergic, inflammatory, and autoimmune diseases including allergic contact dermatitis, atopy, asthma, food allergy, inflammatory bowel diseases, hemolytic anemia, liver injury, leukoderma, and even antitumor immunity. Therefore, the development of in vitro testing alternatives to evaluate in advance whether a substance might lead to the development of these diseases is highly desirable. This review summarizes and discusses recent advances in chemical- and drug-induced allergic, inflammatory, and autoimmune diseases via haptenation and the possible molecular underlying mechanisms, as well as in vitro testing alternatives to evaluate in advance whether a substance might cause the development of these diseases.
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Affiliation(s)
- Eri Sakamoto
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Yasuhiro Katahira
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Izuru Mizoguchi
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Aruma Watanabe
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Yuma Furusaka
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Ami Sekine
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Miu Yamagishi
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Jukito Sonoda
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Satomi Miyakawa
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Shinya Inoue
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Hideaki Hasegawa
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Kazuyuki Yo
- POLA Chemical Industries, Inc., 560 Kashio-cho, Totsuka-ku, Yokohama-shi 244-0812, Kanagawa, Japan
| | - Fumiya Yamaji
- POLA Chemical Industries, Inc., 560 Kashio-cho, Totsuka-ku, Yokohama-shi 244-0812, Kanagawa, Japan
| | - Akemi Toyoda
- POLA Chemical Industries, Inc., 560 Kashio-cho, Totsuka-ku, Yokohama-shi 244-0812, Kanagawa, Japan
| | - Takayuki Yoshimoto
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
- Correspondence: ; Tel.: +81-3-3351-6141
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Ribeiro BE, Breves J, de Souza HSP. Pathogenesis: Crohn’s disease and ulcerative colitis. NATURAL PLANT PRODUCTS IN INFLAMMATORY BOWEL DISEASES 2023:9-46. [DOI: 10.1016/b978-0-323-99111-7.00002-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Vaghari-Tabari M, Moein S, Alipourian A, Qujeq D, Malakoti F, Alemi F, Yousefi B, Khazaie S. Melatonin and inflammatory bowel disease: From basic mechanisms to clinical application. Biochimie 2022; 209:20-36. [PMID: 36535545 DOI: 10.1016/j.biochi.2022.12.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 10/25/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
Inflammatory bowel disease is a chronic inflammatory disease and has periods of recurrence and remission. Improper immune responses to gut flora bacteria, along with genetic susceptibility, appear to be involved in causing this complex disease. It seems dysbiosis and oxidative stress may also be involved in IBD pathogenesis. A significant number of clinical studies have shown an interesting association between sleep disturbances and IBD. Studies in animal models have also shown that sleep deprivation has a significant effect on the pathogenesis of IBD and can aggravate inflammation. These interesting findings have drawn attention to melatonin, a sleep-related hormone. Melatonin is mainly produced by the pineal gland, but many tissues in the body, including the intestines, can produce it. Melatonin can have an interesting effect on the pathogenesis of IBD. Melatonin can enhance the intestinal mucosal barrier, alter the composition of intestinal bacteria in favor of bacteria with anti-inflammatory properties, regulate the immune response, alleviate inflammation and attenuate oxidative stress. It seems that, melatonin supplementation is effective in relieving inflammation and healing intestinal ulcers in IBD animal models. Some clinical studies have also shown that melatonin supplementation as an adjuvant therapy may be helpful in reducing disease activity in IBD patients. In this review article, in addition to reviewing the effects of sleep disturbances and melatonin on key mechanisms involved in the pathogenesis of IBD, we will review the findings of clinical studies regarding the effects of melatonin supplementation on IBD treatment.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Moein
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Alipourian
- Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Faezeh Malakoti
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Forough Alemi
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Bahman Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Sepideh Khazaie
- Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Han H, Liu L, Zhang J, Zhang M, Chen X, Huang Y, Ma W, Qin H, Shen L, Zhang J, Yang W. New Lactobacillus plantarum membrane proteins (LpMPs) towards oral anti-inflammatory agents against dextran sulfate sodium-induced colitis. Int Immunopharmacol 2022; 113:109416. [DOI: 10.1016/j.intimp.2022.109416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 10/24/2022] [Accepted: 10/30/2022] [Indexed: 11/10/2022]
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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: 82] [Impact Index Per Article: 27.3] [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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Kreiss L, Thoma OM, Lemire S, Lechner K, Carlé B, Dilipkumar A, Kunert T, Scheibe K, Heichler C, Merten AL, Weigmann B, Neufert C, Hildner K, Vieth M, Neurath MF, Friedrich O, Schürmann S, Waldner MJ. Label-Free Characterization and Quantification of Mucosal Inflammation in Common Murine Colitis Models With Multiphoton Imaging. Inflamm Bowel Dis 2022; 28:1637-1646. [PMID: 35699622 PMCID: PMC9629455 DOI: 10.1093/ibd/izac114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Clinical challenges in inflammatory bowel diseases require microscopic in vivo evaluation of inflammation. Here, label-free imaging holds great potential, and recently, our group demonstrated the advantage of using in vivo multiphoton endomicroscopy for longitudinal animal studies. This article extends our previous work by in-depth analysis of label-free tissue features in common colitis models quantified by the multiphoton colitis score (MCS). METHODS Fresh mucosal tissues were evaluated from acute and chronic dextran sulfate sodium (DSS), TNBS, oxazolone, and transfer colitis. Label-free imaging was performed by using second harmonic generation and natural autofluorescence. Morphological changes in mucosal crypts, collagen fibers, and cellularity in the stroma were analyzed and graded. RESULTS Our approach discriminated between healthy (mean MCS = 2.5) and inflamed tissue (mean MCS > 5) in all models, and the MCS was validated by hematoxylin and eosin scoring of the same samples (85.2% agreement). Moreover, specific characteristics of each phenotype were identified. While TNBS, oxazolone, and transfer colitis showed high cellularity in stroma, epithelial damage seemed specific for chronic, acute DSS and transfer colitis. Crypt deformations were mostly observed in acute DSS. CONCLUSIONS Quantification of label-free imaging is promising for in vivo endoscopy. In the future, this could be valuable for monitoring of inflammatory pathways in murine models, which is highly relevant for the development of new inflammatory bowel disease therapeutics.
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Affiliation(s)
- Lucas Kreiss
- Address correspondence to: Lucas Kreiss, Dr.-Ing, Institute of Medical Biotechnology, Paul-Gordan-Str 3, 91052 Erlangen, Germany ()
| | | | - Sarah Lemire
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Kristina Lechner
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Birgitta Carlé
- Institute of Medical Biotechnology, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany
| | - Ashwathama Dilipkumar
- Institute of Medical Biotechnology, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany,Erlangen Graduate School in Advanced Optical Technologies, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany
| | - Timo Kunert
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Kristina Scheibe
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Christina Heichler
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Anna-Lena Merten
- Institute of Medical Biotechnology, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany,Erlangen Graduate School in Advanced Optical Technologies, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany
| | - Benno Weigmann
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Clemens Neufert
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Kai Hildner
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany,Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Oliver Friedrich
- Institute of Medical Biotechnology, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany,Erlangen Graduate School in Advanced Optical Technologies, Friedrich-Alexander UniversityErlangen-Nürnberg, Erlangen, Germany
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Han Y, Itenberg SA, Wu X, Xiao H. Guidelines for inflammation models in mice for food components. EFOOD 2022. [DOI: 10.1002/efd2.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Yanhui Han
- Department of Food Science University of Massachusetts Amherst Amherst Massachusetts USA
| | - Sasha A. Itenberg
- Department of Kinesiology, Nutrition, and Health Miami University Oxford Ohio USA
| | - Xian Wu
- Department of Kinesiology, Nutrition, and Health Miami University Oxford Ohio USA
| | - Hang Xiao
- Department of Food Science University of Massachusetts Amherst Amherst Massachusetts USA
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Lu Q, Yang MF, Liang YJ, Xu J, Xu HM, Nie YQ, Wang LS, Yao J, Li DF. Immunology of Inflammatory Bowel Disease: Molecular Mechanisms and Therapeutics. J Inflamm Res 2022; 15:1825-1844. [PMID: 35310454 PMCID: PMC8928114 DOI: 10.2147/jir.s353038] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/26/2022] [Indexed: 12/12/2022] Open
Abstract
As a main digestive organ and an important immune organ, the intestine plays a vital role in resisting the invasion of potential pathogens into the body. Intestinal immune dysfunction remains important pathogenesis of inflammatory bowel disease (IBD). In this review, we explained the interactions among symbiotic flora, intestinal epithelial cells, and the immune system, clarified the operating mechanism of the intestinal immune system, and highlighted the immunological pathogenesis of IBD, with a focus on the development of immunotherapy for IBD. In addition, intestinal fibrosis is a significant complication in patients with long-term IBD, and we reviewed the immunological pathogenesis involved in the development of intestinal fibrogenesis and provided novel antifibrotic immunotherapies for IBD.
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Affiliation(s)
- Quan Lu
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, People’s Republic of China
- Department of Gastroenterology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Mei-feng Yang
- Department of Hematology, Yantian District People’s Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Yu-jie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Jing Xu
- Department of Gastroenterology and Hepatology, Guangzhou First People’s Hospital (School of Medicine of South China University of Technology), Guangzhou, Guangdong, People’s Republic of China
| | - Hao-ming Xu
- Department of Gastroenterology and Hepatology, Guangzhou First People’s Hospital (School of Medicine of South China University of Technology), Guangzhou, Guangdong, People’s Republic of China
| | - Yu-qiang Nie
- Department of Gastroenterology and Hepatology, Guangzhou First People’s Hospital (School of Medicine of South China University of Technology), Guangzhou, Guangdong, People’s Republic of China
| | - Li-sheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, People’s Republic of China
- Department of Gastroenterology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, People’s Republic of China
- Department of Gastroenterology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - De-feng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, People’s Republic of China
- Department of Gastroenterology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
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Safwat El-Deeb O, El-Esawy RO, Al-Shenawy HA, Ghanem HB. Modulating gut dysbiosis and mitochondrial dysfunction in oxazolone-induced ulcerative colitis: the restorative effects of β-glucan and/or celastrol. Redox Rep 2022; 27:60-69. [PMID: 35246012 PMCID: PMC8903761 DOI: 10.1080/13510002.2022.2046425] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objectives Microbiome–Mitochondria interaction is gaining a significant attention; thus, studying its mechanism emerges as a must to provide restorative lines in managing diseases. The aim is to study the mechanistic effects of β-Glucan and/or Celastrol in oxazolone-induced ulcerative colitis (UC). Methods 75 Wistar rats were allocated into 5 equal groups. Group I: control group. Group II: UC group, Group III: β-Glucan-treated UC group, Group IV: Celastrol-treated UC group & Group V: mutual treatment group. All groups were subjected to the detection of free fatty acid receptor 2 (FFAR-2) and peroxisome proliferator-activated receptor gamma co-activator1α (PGC-1α) mRNA gene expressions. Citrate synthase (CS) activity, mitochondrial membrane potential (MMP), ATP concentration, reactive oxygen species (ROS) were detected. Trimethylamine N-oxide (TMAO) concentration was measured. Results After treatment we monitored significant upregulation of FFAR-2 and PGC-1α mRNA expression. Likewise, ATP level and CS activity were significantly increased. On the contrary, there was a significant lessening in ROS and TMAO levels with improvement of MMP. Conclusion Mutual use of β- Glucan and Celastrol had a greater effect than each alone against UC, which is considered a novel finding highlighting the ameliorative effects of this combined treatment in modulating Microbiome/Mitochondria axis, thus launching promising avenues for UC.
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Affiliation(s)
- Omnia Safwat El-Deeb
- Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | | | - Heba Bassiony Ghanem
- Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta, Egypt.,Clinical Laboratory Sciences Department, College of Applied Medical Sciences, Jouf University, Sakaka, Saudi Arabia
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Kanauchi Y, Yamamoto T, Yoshida M, Zhang Y, Lee J, Hayashi S, Kadowaki M. Cholinergic anti-inflammatory pathway ameliorates murine experimental Th2-type colitis by suppressing the migration of plasmacytoid dendritic cells. Sci Rep 2022; 12:54. [PMID: 34997096 PMCID: PMC8742068 DOI: 10.1038/s41598-021-04154-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 12/07/2021] [Indexed: 12/20/2022] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease. Several studies have demonstrated that α7 nicotinic acetylcholine receptors (α7nAChRs) exert anti-inflammatory effects on immune cells and nicotine suppress UC onset and relapse. Plasmacytoid dendritic cells (pDCs) reportedly accumulate in the colon of UC patients. Therefore, we investigated the pathophysiological roles of α7nAChRs on pDCs in the pathology of UC using oxazolone (OXZ)-induced Th2-type colitis with BALB/c mice. 2-deoxy-D-glucose, a central vagal stimulant suppressed OXZ colitis, and nicotine also ameliorated OXZ colitis with suppressing Th2 cytokines, which was reversed by α7nAChR antagonist methyllycaconitine. Additionally, α7nAChRs were expressed on pDCs, which were located very close to cholinergic nerve fibers in the colon of OXZ mice. Furthermore, nicotine suppressed CCL21-induced bone marrow-derived pDC migration due to Rac 1 inactivation, which was reversed by methyllycaconitine, a JAK2 inhibitor AG490 or caspase-3 inhibitor AZ-10417808. CCL21 was mainly expressed in the isolated lymphoid follicles (ILFs) of the colon during OXZ colitis. The therapeutic effect of cholinergic pathway on OXZ colitis probably through α7nAChRs on pDCs were attributed to the suppression of pDC migration toward the ILFs. Therefore, the activation of α7nAChRs has innovative therapeutic potential for the treatment of UC.
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Affiliation(s)
- Yuya Kanauchi
- Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Takeshi Yamamoto
- Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Minako Yoshida
- Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Yue Zhang
- Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Jaemin Lee
- Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Shusaku Hayashi
- Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Makoto Kadowaki
- Division of Gastrointestinal Pathophysiology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
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Adriana Estrella GR, María Eva GT, Alberto HL, María Guadalupe VD, Azucena CV, Sandra OS, Noé AV, Francisco Javier LM. Limonene from Agastache mexicana essential oil produces antinociceptive effects, gastrointestinal protection and improves experimental ulcerative colitis. JOURNAL OF ETHNOPHARMACOLOGY 2021; 280:114462. [PMID: 34324951 DOI: 10.1016/j.jep.2021.114462] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/09/2021] [Accepted: 07/24/2021] [Indexed: 05/27/2023]
Abstract
ETHNOPHARMACOLOGY RELEVANCE Agastache mexicana is a popular plant of great demand in folk medicine, essentially due to its calming properties and for alleviating arthritic, muscular and abdominal pain. Despite its spectrum for pain relief, pharmacological studies of its bioactive constituents have been barely investigated. AIM OF THE STUDY To evaluate protective properties of the A. mexicana and bioactive compounds improving pathological gastrointestinal conditions in rodents. MATERIAL AND METHODS Different doses of the essential oil of A. mexicana ssp. mexicana and ssp. xolocotziana (30-562.2 mg/kg, i.p.) and individual monoterpenes (3-300 mg/kg, i.p.) were evaluated in an abdominal pain model. The most active monoterpene limonene and sulfasalazine (reference drug, 100 mg/kg, p.o.) were also evaluated in the oxazolone-induced colitis model using an oral gavage, where some inflammatory cytokines were analyzed by enzyme-linked immunosorbent assays. Finally, colonic histological assessment and gastroprotection in the absolute ethanol-induced ulcer model were explored. RESULTS Our results demonstrated that the essential oil of both subspecies produced a significant reduction in the abdominal writhes, where monoterpenes limonene and pulegone were partially responsible bioactive metabolites. Limonene showed the major antinociceptive efficacy in the writhing test. It also significantly decreased hyperalgesia, pathological biomarkers, and colonic inflammatory cytokines in the oxazolone-induced colitis model, as well as prevention in gastric damage. CONCLUSIONS Present results provide scientific evidence to reinforce the use of A. mexicana in the traditional medicine for gastrointestinal conditions, mainly related to pain and inflammation, demonstrating the potential of monoterpenes as natural products in the therapeutics of gastrointestinal affections such as ulcer, colitis, and abdominal pain.
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Affiliation(s)
- González-Ramírez Adriana Estrella
- Laboratorio de Neurofarmacología de Productos Naturales de la Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco 101, Col. San Lorenzo Huipulco, C.P. 14370, CDMX, Mexico; Departamento de Farmacobiología, CINVESTAV-IPN, Calzada de los Tenorios 235, Col. Granjas Coapa, C.P. 14330, CDMX, Mexico.
| | - González-Trujano María Eva
- Laboratorio de Neurofarmacología de Productos Naturales de la Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco 101, Col. San Lorenzo Huipulco, C.P. 14370, CDMX, Mexico.
| | - Hernandez-Leon Alberto
- Laboratorio de Neurofarmacología de Productos Naturales de la Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco 101, Col. San Lorenzo Huipulco, C.P. 14370, CDMX, Mexico.
| | - Valle-Dorado María Guadalupe
- Laboratorio de Neurofarmacología de Productos Naturales de la Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco 101, Col. San Lorenzo Huipulco, C.P. 14370, CDMX, Mexico.
| | - Carballo-Villalobos Azucena
- Departamento de Química Inorgánica y Nuclear, Facultad de Química, Universidad Nacional Autónoma de México, Investigación Científica 70, C.U., Coyoacán, 04510, CDMX, Mexico.
| | - Orozco-Suárez Sandra
- Unidad de Investigación Médica en Enfermedades Neurológicas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, Av. Cuauhtémoc 330, Col. Doctores, 06720, CDMX, Mexico.
| | - Alvarado-Vásquez Noé
- Departamento de Bioquímica, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calz. de Tlalpan 04502, Col. Sección XVI, 14080, CDMX, Mexico.
| | - López-Muñoz Francisco Javier
- Departamento de Farmacobiología, CINVESTAV-IPN, Calzada de los Tenorios 235, Col. Granjas Coapa, C.P. 14330, CDMX, Mexico.
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Type 2 immunity in intestinal homeostasis and inflammatory bowel disease. Biochem Soc Trans 2021; 49:2371-2380. [PMID: 34581755 PMCID: PMC8589436 DOI: 10.1042/bst20210535] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/06/2021] [Accepted: 09/09/2021] [Indexed: 12/15/2022]
Abstract
Type 2 immune responses commonly emerge during allergic reactions or infections with helminth parasites. Most of the cytokines associated with type 2 immune responses are IL-4, IL-5, and IL13, which are mainly produced by T helper 2 cells (TH2), eosinophils, basophils, mast cells, and group 2 innate lymphoid cells (ILC2s). Over the course of evolution, humans have developed type 2 immune responses to fight infections and to protect tissues from the potential collateral damage caused by inflammation. For example, worm parasites induce potent type 2 immune responses, which are needed to simultaneously clear the pathogen and to promote tissue repair following injury. Due to the strong type 2 immune responses induced by helminths, which can promote tissue repair in the damaged epithelium, their use has been suggested as a possible treatment for inflammatory bowel disease (IBD); however, the role of type 2 immune responses in the initiation and progression of IBD is not fully understood. In this review, we discuss the molecular and cellular mechanisms that regulate type 2 immune responses during intestinal homeostasis, and we briefly discuss the scarce evidence linking type 2 immune responses with the aetiology of IBD.
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Jacobs I, Ceulemans M, Wauters L, Breynaert C, Vermeire S, Verstockt B, Vanuytsel T. Role of Eosinophils in Intestinal Inflammation and Fibrosis in Inflammatory Bowel Disease: An Overlooked Villain? Front Immunol 2021; 12:754413. [PMID: 34737752 PMCID: PMC8560962 DOI: 10.3389/fimmu.2021.754413] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 09/30/2021] [Indexed: 12/20/2022] Open
Abstract
Eosinophils are leukocytes which reside in the gastrointestinal tract under homeostatic conditions, except for the esophagus which is normally devoid of eosinophils. Research on eosinophils has primarily focused on anti-helminth responses and type 2 immune disorders. In contrast, the search for a role of eosinophils in chronic intestinal inflammation and fibrosis has been limited. With a shift in research focus from adaptive to innate immunity and the fact that the eosinophilic granules are filled with inflammatory mediators, eosinophils are becoming a point of interest in inflammatory bowel diseases. In the current review we summarize eosinophil characteristics and recruitment as well as the current knowledge on presence, inflammatory and pro-fibrotic functions of eosinophils in inflammatory bowel disease and other chronic inflammatory conditions, and we identify research gaps which should be covered in the future.
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Affiliation(s)
- Inge Jacobs
- Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Matthias Ceulemans
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Lucas Wauters
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Christine Breynaert
- Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, Katholieke Universiteit Leuven, Leuven, Belgium
- Department of General Internal Medicine, Allergy and Clinical Immunology, University Hospitals Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Bram Verstockt
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Tim Vanuytsel
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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Wang W, Xu C, Li X, Wang Z, Yang J, Shen Y, Shi M, Chen L, Zhang L, Guo Y, Wang B, Zhang T, Pu Y. Exploration of the potential mechanism of Banxia Xiexin Decoction for the effects on TNBS-induced ulcerative colitis rats with the assistance of network pharmacology analysis. JOURNAL OF ETHNOPHARMACOLOGY 2021; 277:114197. [PMID: 34004261 DOI: 10.1016/j.jep.2021.114197] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 05/01/2021] [Accepted: 05/06/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Banxia Xiexin Decoction (BXD), an ancient TCM prescription originating from Treatise on Febrile Diseases (Shang Han Lun) of the Han Dynasty, has been widely used in modern clinical practice, especially for gastrointestinal diseases, including ulcerative colitis (UC). However, the modern decoction method of BXD differs from that of the original method. Thus, an exploration of the influence of the different decoction methods on the pharmacological effects is interesting and significant. AIM OF THE STUDY This study aimed to systematically compare the pharmacological effects of extracts of BXD on TNBS induce UC rats that were prepared by different methods, the ancient method and the modern method. The findings may provide important information for the further mechanical exploration of the classical prescription, contributing to the rational application and enhancing the understanding of BXD in modern applications or scientific research. METHODS Fifty-four SD rats were randomly divided into the following nine groups at n = 6/group: control group; model group; salicylazosulfapyridine group; BXD ancient extraction method's low-dose group (BXD-AED-L, 3.6 g BXD-AED/kg), medium-dose group (BXD-AED-M, 7.2 g BXD-AED/kg), and high-dose group (BXD-AED-H, 14.4 g BXD-AED/kg); and BXD modern extraction method's low-dose group (BXD-MED-L, 1 g BXD-MED/kg), medium-dose group (BXD-MED-M, 2 g BXD-MED/kg), and high-dose group (BXD-MED-H, 4 g BXD-MED/kg). All the groups, except the control group, were rectally injected with 70 mg/kg ethanol solution containing TNBS (2,4,6-trinitrobenzenesulfonic acid) to establish the UC models. The pharmacological evaluations including disease activity index, colon weight index, macroscopic and histological evaluation of colon damage, and inflammatory cytokine levels (IL-4, IL-10, IL-1β, TNF-α, and IL-6)were measured. In the network pharmacology analysis, the "herbs-components-targets-disease" network was constructed and visually analyzed with which the targets with a strong correlation with UC were screened out. RESULTS The results showed that both BXD-AED and BXD-MED might alleviate the severity of UC with different degrees according to the majority of indices that were evaluated. At similar doses, the BXD-AED groups performed better compared with the BXD-MED groups. With the assistance of the network pharmacology analysis, some key active components (quercetin, baicalein, wogonin, and baicalin) related to the anti-UC/inflammation were screened out. The contents of the components in BXD-AED were higher than those in BXD-MED. The joint results of the study indicated that BXD, an ancient TCM compound prescription, is an effective drug candidate for the modern treatment of UC.
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Affiliation(s)
- Weiwei Wang
- Experiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Congcong Xu
- Experiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xinye Li
- Experiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zibing Wang
- Experiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jinchuan Yang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ye Shen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Mengge Shi
- Experiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lixia Chen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lili Zhang
- Experiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yilin Guo
- Experiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Bing Wang
- Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai, 201203, China
| | - Tong Zhang
- Experiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yiqiong Pu
- Experiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Girish N, Liu CY, Gadeock S, Gomez ML, Huang Y, Sharifkhodaei Z, Washington MK, Polk DB. Persistence of Lgr5+ colonic epithelial stem cells in mouse models of inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 2021; 321:G308-G324. [PMID: 34260310 PMCID: PMC8461791 DOI: 10.1152/ajpgi.00248.2020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/02/2021] [Accepted: 07/12/2021] [Indexed: 02/08/2023]
Abstract
Intestinal mucosal healing is the primary therapeutic goal of medical treatments for inflammatory bowel disease (IBD). Epithelial stem cells are key players in the healing process. Lgr5+ stem cells maintain cellular turnover during homeostasis in the colonic crypt. However, they are lost and dispensable for repair in a wide variety of injury models, including dextran sulfate sodium (DSS) colitis, radiation, helminth infection, and T-cell activation. The direct loss of Lgr5+ cells activates a plasticity response in the epithelium in which other cell types can serve as stem cells. Whether this paradigm applies to mouse models of IBD remains unknown. In contrast to previously tested models, IBD models involve an inflammatory response rooted in the loss of immunologic tolerance to intestinal luminal contents including the microbiome. Here, we show the persistence of Lgr5+ cells in oxazolone, 2,4,6-trinitrobenzene sulfonic acid (TNBS), and Il10-/-, and Il10-/- Tnfr1-/- IBD models. This contrasts with results obtained from DSS-induced injury. Through high-throughput expression profiling, we find that these colitis models were associated with distinct patterns of cytokine expression. Direct exposure of colonic epithelial organoids to DSS, oxazolone, or TNBS resulted in increased apoptosis and loss of Lgr5+ cells. Targeted ablation of Lgr5+ cells resulted in severe exacerbation of chronic, antibody-induced IL-10-deficient colitis, but had only modest effects in TNBS-induced colitis. These results show that distinct mouse models of IBD-like colitis induce different patterns of Lgr5+ stem cell retention and function.NEW & NOTEWORTHY Acute intestinal injury and epithelial repair are associated with the loss of fast-cycling Lgr5+ stem cells and plasticity in the activation of formerly quiescent cell populations. In contrast, here we show in murine inflammatory bowel disease the persistence of the Lgr5+ stem cell population and its essential role in restricting the severity of chronic colitis. This demonstrates a diversity of stem cell responses to colitis.
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Affiliation(s)
- Nandini Girish
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, UC University of California San Diego School of Medicine, San Diego, California
| | - Cambrian Y Liu
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Safina Gadeock
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, UC University of California San Diego School of Medicine, San Diego, California
| | - Marie L Gomez
- Department of Biochemistry & Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Ying Huang
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
| | - Zohreh Sharifkhodaei
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, UC University of California San Diego School of Medicine, San Diego, California
| | - M Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - D Brent Polk
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, UC University of California San Diego School of Medicine, San Diego, California
- Department of Biochemistry & Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California
- Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California
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Restorative effects of Rg3-enriched Korean red ginseng and Persicaria tinctoria extract on oxazolone-induced ulcerative colitis in mice. J Ginseng Res 2021; 46:628-635. [PMID: 36090686 PMCID: PMC9459072 DOI: 10.1016/j.jgr.2021.07.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 07/01/2021] [Accepted: 07/07/2021] [Indexed: 12/01/2022] Open
Abstract
Background Ulcerative colitis (UC) is the large intestine disease that results in chronic inflammation and ulcers in the colon. Rg3-enriched Korean Red Ginseng extract (Rg3-RGE) is known for its pharmacological activities. Persicaria tinctoria (PT) is also used in the treatment of various inflammatory diseases. The aim of this study is to investigate the attenuating effects of Rg3-RGE with PT on oxazolone (OXA)-induced UC in mice. Methods A total of six groups of mice including control group, OXA (as model group, 1.5%) group, sulfasalazine (75 mg/kg) group, Rg3-RGE (20 mg/kg) group, PT (300 mg/kg) group, and Rg3-RGE (10 mg/kg) with PT (150 mg/kg) group. Data on the colon length, body weight, disease activity index (DAI), histological changes, nitric oxide (NO) assay, Real-time PCR of inflammatory factors, ELISA of inflammatory factors, Western blot, and flow cytometry analysis were obtained. Results Overall, the combination treatment of Rg3-RGE and PT significantly improved the colon length and body weight and decreased the DAI in mice compared with the treatment with OXA. Additionally, the histological injury was also reduced by the combination treatment. Moreover, the NO production level and inflammatory mediators and cytokines were significantly downregulated in the Rg3-RGE with the PT group compared with the model group. Also, NLR family pyrin domain containing 3 (NLRP3) inflammasome and nuclear factor kappa B (NF-κB) were suppressed in the combination treatment group compared with the OXA group. Furthermore, the number of immune cell subtypes of CD4+ T-helper cells, CD19+ B-cells, and CD4+ and CD25+ regulatory T-cells (Tregs) was improved in the Rg3-RGE with the PT group compared with the OXA group. Conclusion Overall, the mixture of Rg3-RGE and PT is an effective therapeutic treatment for UC.
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Gensollen T, Lin X, Zhang T, Pyzik M, See P, Glickman JN, Ginhoux F, Waldor M, Salmi M, Rantakari P, Blumberg RS. Embryonic macrophages function during early life to determine invariant natural killer T cell levels at barrier surfaces. Nat Immunol 2021; 22:699-710. [PMID: 34040226 PMCID: PMC8171892 DOI: 10.1038/s41590-021-00934-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 04/16/2021] [Indexed: 12/24/2022]
Abstract
It is increasingly recognized that immune development within mucosal tissues is under the control of environmental factors during early life. However, the cellular mechanisms that underlie such temporally and regionally restrictive governance of these processes are unclear. Here, we uncover an extrathymic pathway of immune development within the colon that is controlled by embryonic but not bone marrow-derived macrophages, which determines the ability of these organs to receive invariant natural killer T (iNKT) cells and allow them to establish local residency. Consequently, early-life perturbations of fetal-derived macrophages result in persistent decreases of mucosal iNKT cells and is associated with later-life susceptibility or resistance to iNKT cell-associated mucosal disorders. These studies uncover a host developmental program orchestrated by ontogenically distinct macrophages that is regulated by microbiota, and they reveal an important postnatal function of macrophages that emerge in fetal life.
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Affiliation(s)
- Thomas Gensollen
- Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Xi Lin
- Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Ting Zhang
- Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA,Howard Hughes Medical Institute, Boston, MA 02115, USA
| | - Michal Pyzik
- Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Peter See
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
| | - Jonathan N. Glickman
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
| | - Florent Ginhoux
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore
| | - Matthew Waldor
- Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA,Howard Hughes Medical Institute, Boston, MA 02115, USA
| | - Marko Salmi
- Institute of Biomedicine, University of Turku, Turku, FI-20520, Finland,MediCity Research Laboratory, University of Turku, Turku, FI-20520, Finland
| | - Pia Rantakari
- Institute of Biomedicine, University of Turku, Turku, FI-20520, Finland,Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, FI-20520, Finland
| | - Richard S. Blumberg
- Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA,Correspondence to:
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Gonzalez Acera M, Patankar JV, Diemand L, Siegmund B, Neurath MF, Wirtz S, Becker C. Comparative Transcriptomics of IBD Patients Indicates Induction of Type 2 Immunity Irrespective of the Disease Ideotype. Front Med (Lausanne) 2021; 8:664045. [PMID: 34136502 PMCID: PMC8200538 DOI: 10.3389/fmed.2021.664045] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/04/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory cytokines initiate and sustain the perpetuation of processes leading to chronic inflammatory conditions such as inflammatory bowel diseases (IBD). The nature of the trigger causing an inflammatory reaction decides whether type 1, type 17, or type 2 immune responses, typically characterized by the respective T- helper cell subsets, come into effect. In the intestine, Type 2 responses have been linked with mucosal healing and resolution upon an immune challenge involving parasitic infections. However, type 2 cytokines are frequently elevated in certain types of IBD in particular ulcerative colitis (UC) leading to the assumption that Th2 cells might critically support the pathogenesis of UC raising the question of whether such elevated type 2 responses in IBD are beneficial or detrimental. In line with this, previous studies showed that suppression of IL-13 and other type 2 related molecules in murine models could improve the outcomes of intestinal inflammation. However, therapeutic attempts of neutralizing IL-13 in ulcerative colitis patients have yielded no benefits. Thus, a better understanding of the role of type 2 cytokines in regulating intestinal inflammation is required. Here, we took a comparative transcriptomic approach to address how Th2 responses evolve in different mouse models of colitis and human IBD datasets. Our data show that type 2 immune-related transcripts are induced in the inflamed gut of IBD patients in both Crohn's disease and UC and across widely used mouse models of IBD. Collectively our data implicate that the presence of a type 2 signature rather defines a distinct state of intestinal inflammation than a disease-specific pathomechanism.
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Affiliation(s)
- Miguel Gonzalez Acera
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Jay V Patankar
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Leonard Diemand
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Britta Siegmund
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Berlin, Germany
| | - Markus F Neurath
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Stefan Wirtz
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Christoph Becker
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
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Wang J, Lin S, Brown JM, van Wagoner D, Fiocchi C, Rieder F. Novel mechanisms and clinical trial endpoints in intestinal fibrosis. Immunol Rev 2021; 302:211-227. [PMID: 33993489 DOI: 10.1111/imr.12974] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 04/18/2021] [Accepted: 04/23/2021] [Indexed: 12/13/2022]
Abstract
The incidence of inflammatory bowel diseases (IBD) worldwide has resulted in a global public health challenge. Intestinal fibrosis leading to stricture formation and bowel obstruction is a frequent complication in Crohn's disease (CD), and the lack of anti-fibrotic therapies makes elucidation of fibrosis mechanisms a priority. Progress has shown that mesenchymal cells, cytokines, microbial products, and mesenteric adipocytes are jointly implicated in the pathogenesis of intestinal fibrosis. This recent information puts prevention or reversal of intestinal strictures within reach through innovative therapies validated by reliable clinical trial endpoints. Here, we review the role of immune and non-immune components of the pathogenesis of intestinal fibrosis, including new cell clusters, cytokine networks, host-microbiome interactions, creeping fat, and their translation for endpoint development in anti-fibrotic clinical trials.
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Affiliation(s)
- Jie Wang
- Henan Key Laboratory of Immunology and Targeted Drug, Xinxiang Medical University, Xinxiang, China.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Sinan Lin
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.,Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jonathan Mark Brown
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - David van Wagoner
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Claudio Fiocchi
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.,Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.,Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
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Involvement of Smad7 in Inflammatory Diseases of the Gut and Colon Cancer. Int J Mol Sci 2021; 22:ijms22083922. [PMID: 33920230 PMCID: PMC8069188 DOI: 10.3390/ijms22083922] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 03/30/2021] [Accepted: 04/07/2021] [Indexed: 02/07/2023] Open
Abstract
In physiological conditions, the human intestinal mucosa is massively infiltrated with various subsets of immune cells, the activity of which is tightly regulated by several counter-regulatory factors. One of these factors is transforming growth factor-β1 (TGF-β1), a cytokine produced by multiple cell types and targeting virtually all the intestinal mucosal cells. Binding of TGF-β1 to its receptors triggers Smad2/3 signaling, thus culminating in the attenuation/suppression of immune–inflammatory responses. In patients with Crohn’s disease and patients with ulcerative colitis, the major human inflammatory bowel diseases (IBD), and in mice with IBD-like colitis, there is defective TGF-β1/Smad signaling due to high levels of the intracellular inhibitor Smad7. Pharmacological inhibition of Smad7 restores TGF-β1 function, thereby reducing inflammatory pathways in patients with IBD and colitic mice. On the other hand, transgenic over-expression of Smad7 in T cells exacerbates colitis in various mouse models of IBD. Smad7 is also over-expressed in other inflammatory disorders of the gut, such as refractory celiac disease, necrotizing enterocolitis and cytomegalovirus-induced colitis, even though evidence is still scarce and mainly descriptive. Furthermore, Smad7 has been involved in colon carcinogenesis through complex and heterogeneous mechanisms, and Smad7 polymorphisms could influence cancer prognosis. In this article, we review the data about the expression and role of Smad7 in intestinal inflammation and cancer.
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Osikov MV, Simonyan EV, Boyko MS, Ogneva OI, Ilyinykh MA, Vorgova LV, Bogomolova AM. Effect of Vitamin D3 in Composition of Original Rectal Suppositories on Parameter of Protein Oxidative Modification in Large Intestine in Experimental Ulcerative Colitis. Bull Exp Biol Med 2021; 170:608-612. [PMID: 33788108 DOI: 10.1007/s10517-021-05116-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Indexed: 11/30/2022]
Abstract
The effect of vitamin D3 in the composition of original rectal suppositories on the content of products of oxidative modification of proteins in mucous membrane of the large intestine was studied in rats with experimental ulcerative colitis provoked by a two-stage administration of 3% oxazolone. The rectal suppositories with vitamin D3 (1500 IU) were administered every 12 h during 5 days. Condition of the rats was assessed according to disease activity index (DAI), while the content of oxidative modification products of proteins in the homogenate of the mucous membrane was assayed with extraction-spectrophotometric method in the lesion focus of large intestine. DAI increased during entire observation period of ulcerative colitis, which correlated with the level of products of spontaneous and induced oxidative modification of proteins in mucous membrane of the colon. The study examined the pharmaceutical and technological features of novel rectal suppositories of original composition weighing 300 mg, which are based on polyethylene glycol supplemented with aqueous solution of vitamin D3 (10%). The use of rectal suppositories with vitamin D3 reduced DAI and inhibited the oxidative modification of proteins.
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Affiliation(s)
- M V Osikov
- South-Ural State Medical University, Ministry of Health of the Russian Federation, Chelyabinsk, Russia
| | - E V Simonyan
- South-Ural State Medical University, Ministry of Health of the Russian Federation, Chelyabinsk, Russia
| | - M S Boyko
- South-Ural State Medical University, Ministry of Health of the Russian Federation, Chelyabinsk, Russia.
| | - O I Ogneva
- South-Ural State Medical University, Ministry of Health of the Russian Federation, Chelyabinsk, Russia
| | - M A Ilyinykh
- South-Ural State Medical University, Ministry of Health of the Russian Federation, Chelyabinsk, Russia
| | - L V Vorgova
- South-Ural State Medical University, Ministry of Health of the Russian Federation, Chelyabinsk, Russia
| | - A M Bogomolova
- South-Ural State Medical University, Ministry of Health of the Russian Federation, Chelyabinsk, Russia
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Złotkowska D, Stachurska E, Fuc E, Wróblewska B, Mikołajczyk A, Wasilewska E. Differences in Regulatory Mechanisms Induced by β-Lactoglobulin and κ-Casein in Cow's Milk Allergy Mouse Model-In Vivo and Ex Vivo Studies. Nutrients 2021; 13:nu13020349. [PMID: 33503831 PMCID: PMC7911159 DOI: 10.3390/nu13020349] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/19/2021] [Accepted: 01/20/2021] [Indexed: 12/14/2022] Open
Abstract
The presence of various proteins, including modified ones, in food which exhibit diverse immunogenic and sensitizing properties increases the difficulty of predicting host immune responses. Still, there is a lack of sufficiently reliable and comparable data and research models describing allergens in dietary matrices. The aim of the study was to estimate the immunomodulatory effects of β-lactoglobulin (β-lg) in comparison to those elicited by κ-casein (κ-CN), in vivo and ex vivo, using naïve splenocytes and a mouse sensitization model. Our results revealed that the humoral and cellular responses triggered by β-lg and κ-CN were of diverse magnitudes and showed different dynamics in the induction of control mechanisms. β-Lg turned out to be more immunogenic and induced a more dominant Th1 response than κ-CN, which triggered a significantly higher IgE response. For both proteins, CD4+ lymphocyte profiles correlated with CD4+CD25+ and CD4+CD25+Foxp3+ T cells induction and interleukin 10 secretion, but β-lg induced more CD4+CD25+Foxp3- Tregs. Moreover, ex vivo studies showed the risk of interaction of immune responses to different milk proteins, which may exacerbate allergy, especially the one caused by β-lg. In conclusion, the applied model of in vivo and ex vivo exposure to β-lg and κ-CN showed significant differences in immunoreactivity of the tested proteins (κ-CN demonstrated stronger allergenic potential than β-lg), and may be useful for the estimation of allergenic potential of various food proteins, including those modified in technological processes.
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Affiliation(s)
- Dagmara Złotkowska
- Department of Immunology and Food Microbiology, Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10 Str., 10-748 Olsztyn, Poland; (E.S.); (E.F.); (B.W.)
- Correspondence: (D.Z.); (E.W.); Tel.: +48-89-523-46-75 (D.Z.); +48-89-523-46-03 (E.W.)
| | - Emilia Stachurska
- Department of Immunology and Food Microbiology, Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10 Str., 10-748 Olsztyn, Poland; (E.S.); (E.F.); (B.W.)
| | - Ewa Fuc
- Department of Immunology and Food Microbiology, Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10 Str., 10-748 Olsztyn, Poland; (E.S.); (E.F.); (B.W.)
| | - Barbara Wróblewska
- Department of Immunology and Food Microbiology, Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10 Str., 10-748 Olsztyn, Poland; (E.S.); (E.F.); (B.W.)
| | - Anita Mikołajczyk
- Department of Public Health, Faculty of Health Sciences, Collegium Medicum, University of Warmia and Mazury, 10-082 Olsztyn, Poland;
| | - Ewa Wasilewska
- Department of Immunology and Food Microbiology, Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10 Str., 10-748 Olsztyn, Poland; (E.S.); (E.F.); (B.W.)
- Correspondence: (D.Z.); (E.W.); Tel.: +48-89-523-46-75 (D.Z.); +48-89-523-46-03 (E.W.)
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48
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Borowczyk J, Shutova M, Brembilla NC, Boehncke WH. IL-25 (IL-17E) in epithelial immunology and pathophysiology. J Allergy Clin Immunol 2021; 148:40-52. [PMID: 33485651 DOI: 10.1016/j.jaci.2020.12.628] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 12/08/2020] [Accepted: 12/16/2020] [Indexed: 02/07/2023]
Abstract
IL-25, also known as IL-17E, is a unique cytokine of the IL-17 family. Indeed, IL-25 exclusively was shown to strongly induce expression of the cytokines associated with type 2 immunity. Although produced by several types of immune cells, such as T cells, dendritic cells, or group 2 innate lymphoid cells, a vast amount of IL-25 derives from epithelial cells. The functions of IL-25 have been actively studied in the context of physiology and pathology of various organs including skin, airways and lungs, gastrointestinal tract, and thymus. Accumulating evidence suggests that IL-25 is a "barrier surface" cytokine whose expression depends on extrinsic environmental factors and when upregulated may lead to inflammatory disorders such as atopic dermatitis, psoriasis, or asthma. This review summarizes the progress of the recent years regarding the effects of IL-25 on the regulation of immune response and the balance between its homeostatic and pathogenic role in various epithelia. We revisit IL-25's general and tissue-specific mechanisms of action, mediated signaling pathways, and transcription factors activated in immune and resident cells. Finally, we discuss perspectives of the IL-25-based therapies for inflammatory disorders and compare them with the mainstream ones that target IL-17A.
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Affiliation(s)
- Julia Borowczyk
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Maria Shutova
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | | | - Wolf-Henning Boehncke
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Division of Dermatology and Venereology, University Hospitals of Geneva, Geneva, Switzerland.
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Ameliorative Effect of Sinapic Acid on Dextran Sodium Sulfate- (DSS-) Induced Ulcerative Colitis in Kunming (KM) Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:8393504. [PMID: 33312339 PMCID: PMC7719534 DOI: 10.1155/2020/8393504] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 10/11/2019] [Accepted: 10/16/2019] [Indexed: 12/25/2022]
Abstract
Ulcerative colitis is a chronic gastrointestinal disease characterized by intestinal inflammation and serious mucosal damage. As a naturally hydroxycinnamic acid, sinapic acid (SA) has antioxidant, anticancer, and neuroprotective activities. We investigated the anticolitic effect and potential mechanisms of SA in DSS-induced colitis in Kunming (KM) mice. SA treatment significantly reduced body weight loss, colon shortening, and intestinal wall thickening in colitis mice. SA treatment also significantly reduced the histological infiltration of inflammatory cells and decreased myeloperoxidase (MPO) activity in the colons of colitis mice. The administration of SA attenuated oxidative damage by enhancing the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase and reduced the serum and colonic mRNA levels of proinflammatory cytokines in colitis mice. We used qRT-PCR and Western blotting assays and demonstrated that SA reduced the activation of the NLRP3 inflammasome and attenuated intestinal permeability by enhancing the expression of ZO-1, occludin, and claudin-1 in colitis mice. Here, we conclude that SA exhibits great anticolitic activity against DSS-induced colitis by enhancing the activity of antioxidant enzymes, reducing intestinal inflammation, and maintaining the intestinal barrier. Finally, we suggest that SA may be a safe adjuvant for the prevention of clinical colitis.
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Antonioli L, Fornai M, Pellegrini C, Bertani L, Nemeth ZH, Blandizzi C. Inflammatory Bowel Diseases: It's Time for the Adenosine System. Front Immunol 2020; 11:1310. [PMID: 32849492 PMCID: PMC7403190 DOI: 10.3389/fimmu.2020.01310] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 05/22/2020] [Indexed: 12/16/2022] Open
Affiliation(s)
- Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Lorenzo Bertani
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Zoltan H Nemeth
- Department of Surgery, Morristown Medical Center, Morristown, NJ, United States.,Department of Anesthesiology, Columbia University Medical Center, New York, NY, United States
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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