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Patra S, Chaudhary S, Samal SC, Ayyanar P, Padhi S, Nayak HK, Satapathy AK, Nayak S, Sahu A, Parida T, Shahin M. FoxP3-positive T regulatory cells and its effector mechanisms in Crohn's disease: an immunohistochemical and image morphometric analysis on endoscopic mucosal biopsies. Eur J Gastroenterol Hepatol 2025:00042737-990000000-00509. [PMID: 40207496 DOI: 10.1097/meg.0000000000002971] [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] [Indexed: 04/11/2025]
Abstract
OBJECTIVE Crohn's disease (CD) is an immune inflammatory disorder of the gastrointestinal tract arising from a complex interplay of genetic, environmental, microbiome, and immune factors. Regulatory T cells (Tregs), characterized by FoxP3 expression, are crucial for maintaining immune homeostasis through PD-1/PD-L1 interaction, interleukin (IL)-10 release, and granzyme (GrB) production. This study aimed to elucidate the role of FoxP3 positive (+) Tregs in CD. METHODS Segmental colonoscopic biopsies from 46 treatment-naive CD cases (34 adults and 12 children) categorized into noninflamed [n = 32; Nancy histologic index (NHI) 0, 1] and inflamed (n = 100; NHI 2-4) mucosae using NHI. CD4, FoxP3, PD-1, IL-10, and GrB immunoexpression were analyzed by eyeballing and image morphometry. Findings were correlated with activity, granulomas, and skip lesions; and compared with site-matched non-inflammatory bowel disease (IBD) controls (n = 30). RESULTS FoxP3+ Tregs, IL-10, PD-1, and GrB expressions were significantly higher in NHI 3-4 mucosae than in NHI 0-1 and controls (P < 0.05). No significant differences were observed between adults and children, whereas those with granulomas had increased expression (P = 0.045). The FoxP3 : CD4 ratio positively correlated with IL-10 (Spearman, r = 0.307, P = 0.002), GrB (r = 0.302, P = 0.002), but not with PD-1 (r = 0.98, P = 0.33). CONCLUSIONS Our findings point to the possibility of a qualitative defect in FoxP3+ Tregs in CD. The functional arms of Tregs in CD need to be elucidated further in larger prospective cohorts to validate our observations and pave the way for future immunotherapy.
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Affiliation(s)
| | | | | | | | | | | | | | - Saurav Nayak
- Department of Biochemistry, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Ajit Sahu
- Department of Pathology and Laboratory Medicine
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Shim JV, Rehberg M, Wagenhuber B, van der Graaf PH, Chung DW. Combining mechanistic modeling with machine learning as a strategy to predict inflammatory bowel disease clinical scores. Front Pharmacol 2025; 16:1479666. [PMID: 40070575 PMCID: PMC11893853 DOI: 10.3389/fphar.2025.1479666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 01/27/2025] [Indexed: 03/14/2025] Open
Abstract
Disease activity scores are efficacy endpoints in clinical trials of inflammatory bowel disease (IBD) therapies. Crohn's disease activity index (CDAI), Mayo endoscopic score (MES) and Mayo score are frequently used in clinical trials. They rely on either the physician's observation of the inflammatory state of the patient's gastrointestinal tissue alone or combined with the patient's subjective evaluation of general wellbeing. Given the importance of these scores in evaluating the efficacy of drug treatment and disease severity, there has been interest in developing a computational approach to reliably predict these scores. A promising approach is using mechanistic models such as quantitative systems pharmacology (QSP) which simulate the mechanisms of the disease and its modulation by the drug pharmacology. However, extending QSP model simulations to clinical score predictions has been challenging due to the limited availability of gut biopsy measurements and the subjective nature of some of the evaluation criteria for these scores that cannot be described using mechanistic relationships. In this perspective, we examine details of IBD disease activity scores and current progress in building predictive models for these scores (such as biomarkers for disease activity). Then, we propose a method to leverage simulated markers of inflammation from a QSP model to predict IBD clinical scores using a machine learning algorithm. We will demonstrate how this combined approach can be used to (1) explore mechanistic insights underlying clinical observations; and (2) simulate novel therapeutic strategies that could potentially improve clinical outcomes.
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Affiliation(s)
- Jaehee V. Shim
- Certara Applied BioSimulation, Sheffield, United Kingdom
| | - Markus Rehberg
- Sanofi R&D, Translational Disease Modeling, Frankfurt amMain, Germany
| | - Britta Wagenhuber
- Sanofi R&D, Translational Disease Modeling, Frankfurt amMain, Germany
| | - Piet H. van der Graaf
- Certara Applied BioSimulation, Sheffield, United Kingdom
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
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Hu Y, Tang J, Yu D, Su S, Fang J, Xia L, Xu W, Zhu W, Song N, Wang F, Diao D, Zhang W. Correlation and diagnostic significance of CD4 T cell subsets and NLRP3 inflammasome in ulcerative colitis: the role of the NLRP3/T-bet/GATA3 axis. BMC Gastroenterol 2025; 25:23. [PMID: 39833691 PMCID: PMC11748810 DOI: 10.1186/s12876-025-03603-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 01/09/2025] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND AND AIM Ulcerative colitis (UC) is characterized by complex immunological interactions involving CD4 T cell subsets and the NLRP3 inflammasome, which influence inflammatory responses. This investigation focused on delineating the activation profiles of these components and their correlation with disease severity and activity, assessing their diagnostic implications in UC. METHODS We conducted immunohistochemistry and ELISA assays to measure markers expression of CD4 T cell subsets and the NLRP3 inflammasome in UC patients versus controls. Findings were validated using correlation analysis, molecular docking and ROC curves. RESULTS UC patients displayed increased Th1 (T-bet, TNF-α), Th2 (GATA3, IL-6), and Th17 (RORγt, IL-17, IL-22, IL-23) markers versus controls. Additionally, Th1 and Th2 cytokines (IL-2 and IL-4) were significantly elevated in severe UC, while Treg markers (FOXP3, IL-10, TGF-β1) were elevated only in mild-to-moderate UC. Enhanced NLRP3 inflammasome activation, indicated by elevated NLRP3, Caspase-1, and IL-1β levels. These molecular patterns, confirmed through correlation analysis and molecular docking, underscored strong correlations among NLRP3, T-bet, and GATA3, supporting the proposed NLRP3/T-bet/GATA3 axis. This axis, along with other biomarkers, showed strong associations with UC severity, Mayo score, UCEIS, demonstrated relatively high diagnostic value. CONCLUSION The NLRP3/T-bet/GATA3 axis provides a referable strategy for multi-targeted combined treatment of UC and may serve as potential biomarkers for enhancing diagnostic accuracy and guiding therapy.
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Affiliation(s)
- Yingnan Hu
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China.
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
| | - Jingyi Tang
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China
| | - Dian Yu
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China
| | - Shuo Su
- Department of Spleen and Stomach Diseases, Qujiang District Hospital of Traditional Chinese Medicine, Quzhou, China
| | - Jintao Fang
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China
| | - Linying Xia
- Department of Orthopaedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Wenjun Xu
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China
| | - Weihan Zhu
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ninping Song
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, No. 318, Chaowang Road, Gongshu District, Hangzhou City, Zhejiang Province, CN310005, People's Republic of China
| | - Fengyong Wang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, No. 318, Chaowang Road, Gongshu District, Hangzhou City, Zhejiang Province, CN310005, People's Republic of China
| | - Dechang Diao
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
| | - Wei Zhang
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, China.
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, No. 318, Chaowang Road, Gongshu District, Hangzhou City, Zhejiang Province, CN310005, People's Republic of China.
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Nicolò S, Faggiani I, Errico C, D'Amico F, Parigi TL, Danese S, Ungaro F. Translational characterization of immune pathways in inflammatory bowel disease: insights for targeted treatments. Expert Rev Clin Immunol 2025; 21:55-72. [PMID: 39313992 DOI: 10.1080/1744666x.2024.2400300] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 08/30/2024] [Indexed: 09/25/2024]
Abstract
INTRODUCTION The pathogenesis of inflammatory bowel disease (IBD) involves the dysregulation of multiple inflammatory pathways. The understanding of these mechanisms allows their selective targeting for therapeutic purposes. The discovery of Tumor Necrosis Factor-alpha's (TNF-α) role in mucosal inflammation ushered an exciting new era of drug development which now comprises agents targeting multiple pro-inflammatory signaling pathways, integrins, and leukocyte trafficking regulators. AREA COVERED This review provides an overview of the main molecular players of IBD, their translation into therapeutic targets and the successful development of the advanced agents modulating them. We combine basic science with clinical trials data to present a critical review of both the successful and failed drug development programs. A PubMed literature search was conducted to delve into the available literature and clinical trials. EXPERT OPINION The treatment landscape for IBD has rapidly expanded, particularly with the development of biologics targeting TNF-α, integrins, and S1P modulators, as well as newer agents such as IL-12/IL-23 inhibitors and JAK inhibitors, offering robust efficacy and safety profiles. However, challenges persist in understanding and effectively treating difficult-to-treat IBD, highlighting the need for continued research to uncover novel therapeutic targets and optimize patient outcomes.
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Affiliation(s)
- Sabrina Nicolò
- Department of Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Faculty of Medicine, Università Vita-Salute San Raffaele, Milan, Italy
| | - Ilaria Faggiani
- Department of Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Faculty of Medicine, Università Vita-Salute San Raffaele, Milan, Italy
| | - Carmela Errico
- Department of Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Faculty of Medicine, Università Vita-Salute San Raffaele, Milan, Italy
| | - Ferdinando D'Amico
- Department of Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Tommaso Lorenzo Parigi
- Department of Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Faculty of Medicine, Università Vita-Salute San Raffaele, Milan, Italy
| | - Silvio Danese
- Department of Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Faculty of Medicine, Università Vita-Salute San Raffaele, Milan, Italy
| | - Federica Ungaro
- Department of Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Faculty of Medicine, Università Vita-Salute San Raffaele, Milan, Italy
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Liu Z, Wu S, Zhang W, Cui H, Zhang J, Yin X, Zheng X, Shen T, Ying H, Chen L, Wang H, Jiang J. Cordycepin mitigates dextran sulfate sodium-induced colitis through improving gut microbiota composition and modulating Th1/Th2 and Th17/Treg balance. Biomed Pharmacother 2024; 180:117394. [PMID: 39395256 DOI: 10.1016/j.biopha.2024.117394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 08/20/2024] [Accepted: 08/30/2024] [Indexed: 10/14/2024] Open
Abstract
BACKGROUND Imbalances in Th1/Th2 and Th17/Treg immune axes, coupled with disruptions in the gut microbiota (GM), play a pivotal role in the pathogenesis of inflammatory bowel disease (IBD). Cordycepin, a natural anti-inflammatory compound, holds promise in mitigating IBD by rebalancing these immune axes in conjunction with modulating the GM. The aim of this experiment is to investigate the potential of cordycepin in mitigating enteritis and elucidate the underlying mechanisms associated with its ameliorative effects on enteritis. METHODS On the day of inducing experimental colitis with Dextran Sulfate Sodium (DSS), mice in the DSS + Cordycepin and Cordycepin groups received 50 mg/kg/day Cordycepin via intra-gastric administration (i.g.) for seven consecutive days, respectively. Mice in the DSS and control groups were treated with equal volumes of saline. On day 8, all mice were euthanized under pentobarbital sodium anesthesia. RESULTS In a DSS-induced colitis mouse model, Cordycepin treatment led to a significant reduction in the disease activity index (DAI), splenic weight, and colonic pathological injury while simultaneously improving body weight and colonic length. Furthermore, it positively impacted GM composition, resulting in decreased Th1 and Th17 cells, alongside an increase in Th2 and Treg cells. The contents of the mouse colon were extracted for microbial community analysis. Mouse blood was prepared into a single-cell suspension, and flow cytometry was used to assess the expressio of Treg, Th17, Th1, and Th2 immune cells. CONCLUSIONS These results underscored the effective intervention of cordycepin in ameliorating DSS-induced colitis by harmonizing the interplay between GM and immune homeostasis.
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Affiliation(s)
- Zhilin Liu
- Department of Gastrointestinal Surgery, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Institute of Cell Therapy, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Shaoxian Wu
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Institute of Cell Therapy, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Wenting Zhang
- Affiliated Changzhou Children's Hospital of Nantong University, Changzhou Children's Hospital, Changzhou 213003, China
| | - Hengwei Cui
- Department of Gastrointestinal Surgery, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Jingfeng Zhang
- Department of Gastrointestinal Surgery, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Xuan Yin
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Institute of Cell Therapy, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Xiao Zheng
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Institute of Cell Therapy, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Tao Shen
- College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Jiangsu, Nanjing, China
| | - Hanjie Ying
- College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Jiangsu, Nanjing, China
| | - Lujun Chen
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Institute of Cell Therapy, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China.
| | - Haitao Wang
- Department of Gastrointestinal Surgery, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China.
| | - Jingting Jiang
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Institute of Cell Therapy, the Third Affiliated Hospital of Soochow University, Changzhou 213003, China.
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Fang M, Yao J, Zhang H, Sun J, Yin Y, Shi H, Jiang G, Shi X. Specific deletion of Mettl3 in IECs triggers the development of spontaneous colitis and dysbiosis of T lymphocytes in mice. Clin Exp Immunol 2024; 217:57-77. [PMID: 38507548 PMCID: PMC11188546 DOI: 10.1093/cei/uxae025] [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: 06/13/2023] [Revised: 01/23/2024] [Accepted: 03/19/2024] [Indexed: 03/22/2024] Open
Abstract
The enzymatic core component of m6A writer complex, Mettl3, plays a crucial role in facilitating the development and progress of gastric and colorectal cancer (CRC). However, its underlying mechanism in regulating intestinal inflammation remains unclear and poorly investigated. First, the characteristics of Mettl3 expression in inflammatory bowel diseases (IBD) patients were examined. Afterward, we generated the mice line with intestinal epithelial cells (IECs)-specific deletion of Mettl3 verified by various experiments. We continuously recorded and compared the physiological status including survival rate etc. between the two groups. Subsequently, we took advantage of staining assays to analyze mucosal damage and immune infiltration of Mettl3WT and Mettl3KO primary IECs. Bulk RNA sequencing was used to pursuit the differential expression of genes (DEGs) and associated signaling pathways after losing Mettl3. Pyroptosis-related proteins were to determine whether cell death was caused by pyroptosis. Eventually, CyTOF was performed to probe the difference of CD45+ cells, especially CD3e+ T-cell clusters after losing Mettl3. In IBD patients, Mettl3 was highly expressed in the inner-nucleus of IECs while significantly decreased upon acute intestinal inflammation. IECs-specific deletion of Mettl3 KO mice triggered a wasting phenotype and developed spontaneous colitis. The survival rate, body weight, and intestinal length observed from 2 to 8 weeks of Mettl3KO mice were significantly lower than Mettl3WT mice. The degree of mucosal damage and immune infiltration in Mettl3KO were even more serious than in their WT littermate. Bulk RNA sequencing demonstrated that DEGs were dramatically enriched in NOD-signaling pathways due to the loss of Mettl3. The colonic epithelium was more prone to pyroptosis after losing Mettl3. Subsequently, CyTOF revealed that T cells have altered significantly in Mettl3KO. Furthermore, there was abnormal proliferation of CD4+ T and markedly exhaustion of CD8 + T in Mettl3KO mice. In severe IBD patients, Mettl3 is located in the inner-nucleus of IECs and declined when intestinal inflammation occurs. Subsequently, Mettl3 prevented mice from developing colitis.
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Affiliation(s)
- Miao Fang
- School of Medicine, Southeast University, Nanjing, PR China
| | - Jie Yao
- School of Medicine, Southeast University, Nanjing, PR China
- Department of General Surgery, Nantong Haimen People’s Hospital, Nantong, PR China
| | - Haifeng Zhang
- School of Medicine, Southeast University, Nanjing, PR China
| | - Jiahui Sun
- School of Public Health, Southeast University, Nanjing, PR China
| | - Yiping Yin
- School of Medicine, Southeast University, Nanjing, PR China
| | - Hongzhou Shi
- School of Medicine, Southeast University, Nanjing, PR China
| | | | - Xin Shi
- School of Medicine, Southeast University, Nanjing, PR China
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Wen Y, Wang H, Tian D, Wang G. TH17 cell: a double-edged sword in the development of inflammatory bowel disease. Therap Adv Gastroenterol 2024; 17:17562848241230896. [PMID: 38390028 PMCID: PMC10883129 DOI: 10.1177/17562848241230896] [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: 09/16/2023] [Accepted: 01/17/2024] [Indexed: 02/24/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic nonspecific inflammatory disease of the gastrointestinal tract, and its pathogenesis has not been fully understood. Extensive dysregulation of the intestinal mucosal immune system is critical in the development and progression of IBD. T helper (Th) 17 cells have the characteristics of plasticity. They can transdifferentiate into subpopulations with different functions in response to different factors in the surrounding environment, thus taking on different roles in regulating the intestinal immune responses. In this review, we will focus on the plasticity of Th17 cells as well as the function of Th17 cells and their related cytokines in IBD. We will summarize their pathogenic and protective roles in IBD under different conditions, respectively, hoping to further deepen the understanding of the pathological mechanisms underlying IBD and provide insights for future treatment.
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Affiliation(s)
- Yue Wen
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Ge Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
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Cui H, Wang N, Li H, Bian Y, Wen W, Kong X, Wang F. The dynamic shifts of IL-10-producing Th17 and IL-17-producing Treg in health and disease: a crosstalk between ancient "Yin-Yang" theory and modern immunology. Cell Commun Signal 2024; 22:99. [PMID: 38317142 PMCID: PMC10845554 DOI: 10.1186/s12964-024-01505-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 01/28/2024] [Indexed: 02/07/2024] Open
Abstract
The changes in T regulatory cell (Treg) and T helper cell (Th) 17 ratios holds paramount importance in ensuring internal homeostasis and disease progression. Recently, novel subsets of Treg and Th17, namely IL-17-producing Treg and IL-10-producing Th17 have been identified. IL-17-producing Treg and IL-10-producing Th17 are widely considered as the intermediates during Treg/Th17 transformation. These "bi-functional" cells exhibit plasticity and have been demonstrated with important roles in multiple physiological functions and disease processes. Yin and Yang represent opposing aspects of phenomena according to the ancient Chinese philosophy "Yin-Yang" theory. Furthermore, Yin can transform into Yang, and vice versa, under specific conditions. This theory has been widely used to describe the contrasting functions of immune cells and molecules. Therefore, immune-activating populations (Th17, M1 macrophage, etc.) and immune overreaction (inflammation, autoimmunity) can be considered Yang, while immunosuppressive populations (Treg, M2 macrophage, etc.) and immunosuppression (tumor, immunodeficiency) can be considered Yin. However, another important connotation of "Yin-Yang" theory, the conversion between Yin and Yang, has been rarely documented in immune studies. The discovery of IL-17-producing Treg and IL-10-producing Th17 enriches the meaning of "Yin-Yang" theory and further promotes the relationship between ancient "Yin-Yang" theory and modern immunology. Besides, illustrating the functions of IL-17-producing Treg and IL-10-producing Th17 and mechanisms governing their differentiation provides valuable insights into the mechanisms underlying the dynamically changing statement of immune statement in health and diseases.
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Affiliation(s)
- Huantian Cui
- First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Ning Wang
- First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Hanzhou Li
- College of Integrative Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yuhong Bian
- College of Integrative Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Weibo Wen
- First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China.
| | - Xiangying Kong
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Fudi Wang
- The First Affiliated Hospital, Institute of Translational Medicine, The Second Affiliated Hospital, School of Public Health, Cancer Center, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
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Ge L, Liu S, Li S, Yang J, Hu G, Xu C, Song W. Psychological stress in inflammatory bowel disease: Psychoneuroimmunological insights into bidirectional gut–brain communications. Front Immunol 2022; 13:1016578. [PMID: 36275694 PMCID: PMC9583867 DOI: 10.3389/fimmu.2022.1016578] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Inflammatory bowel disease (IBD), mainly including ulcerative colitis (UC) and Crohn’s disease (CD), is an autoimmune gastrointestinal disease characterized by chronic inflammation and frequent recurrence. Accumulating evidence has confirmed that chronic psychological stress is considered to trigger IBD deterioration and relapse. Moreover, studies have demonstrated that patients with IBD have a higher risk of developing symptoms of anxiety and depression than healthy individuals. However, the underlying mechanism of the link between psychological stress and IBD remains poorly understood. This review used a psychoneuroimmunology perspective to assess possible neuro-visceral integration, immune modulation, and crucial intestinal microbiome changes in IBD. Furthermore, the bidirectionality of the brain–gut axis was emphasized in the context, indicating that IBD pathophysiology increases the inflammatory response in the central nervous system and further contributes to anxiety- and depression-like behavioral comorbidities. This information will help accurately characterize the link between psychological stress and IBD disease activity. Additionally, the clinical application of functional brain imaging, microbiota-targeted treatment, psychotherapy and antidepressants should be considered during the treatment and diagnosis of IBD with behavioral comorbidities. This review elucidates the significance of more high-quality research combined with large clinical sample sizes and multiple diagnostic methods and psychotherapy, which may help to achieve personalized therapeutic strategies for IBD patients based on stress relief.
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Affiliation(s)
- Li Ge
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Shuman Liu
- School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Sha Li
- School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Jing Yang
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Guangran Hu
- School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Changqing Xu
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Wengang Song
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- *Correspondence: Wengang Song,
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Luo Y, Liu S, Li H, Hou J, Lin W, Xu Z, Lu T, Li Y, Peng B, Zhang S, Han X, Kuang Z, Wen Y, Cai J, Liu F, Chen XL. Mass Cytometry and Single-Cell Transcriptome Analyses Reveal the Immune Cell Characteristics of Ulcerative Colitis. Front Mol Biosci 2022; 9:859645. [PMID: 35813827 PMCID: PMC9260076 DOI: 10.3389/fmolb.2022.859645] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 06/02/2022] [Indexed: 12/31/2022] Open
Abstract
Background: The pathogenesis of ulcerative colitis (UC) is closely related to immunity. The immune characteristic differences between active UC (UCa) and inactive UC (UCin) have not been completely explained. Mass cytometry (CyTOF) and single-cell RNA sequencing (scRNA-seq) were used to analyze the immune cells of UCa, UCin and healthy control (HC) subjects to determine the specific immune characteristics. Methods: The immune cell subsets among UCa, UCin, HC were distinguished using CyTOF analysis. scRNA-seq analysis was used to validate the results of CyTOF. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to understand the roles of differential immune cell subsets. Results: After CyTOF analysis and validation of scRNA-seq analysis, differential immune cell subsets mainly contained TNF+IL-17A++ effector memory (EM) Tregs, CXCR3+CTLA4+ EM Tregs, CXCR3++CCR7+ B cells, HLA-DR+CCR7+ dendritic cells (DCs) and CTLA-4+ natural killer (NK) cells. In comparison to HC, CCR6+TNF+CD161+ EM T cells were highly enriched in UCa and UCin. Besides, UCa was characterized by an increase in CD38+TNF+ EM Tregs, CXCR3+CCR4+ naïve B cells, HLA-DR+CD14+IL21+ macrophages/monocytes, HLA-DR+CCR7+ DCs, AHR+CD14+ cytotoxic NK (cNK) cells and CD8A+IFNG+ cNK cells. Decreases in CD38+CD27+ plasmablasts, CXCR3+CD38+ regulatory NK cells, and CXCR3+CCR7+ tolerant NK cells in UCa were discovered. Conclusions: Novel immune cell subsets which was used to distinguish UCa, UCin and HC were identified. This information might be utilized to distinguish the patients with UCa and UCin.
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Affiliation(s)
- Yongxin Luo
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shiying Liu
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Huibiao Li
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiangtao Hou
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wenjia Lin
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zewen Xu
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Tianyu Lu
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yanwu Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Pi-Wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bin Peng
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shijing Zhang
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xue Han
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zuoliang Kuang
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi Wen
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiazhong Cai
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Pi-Wei Institute, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fengbin Liu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Fengbin Liu, ; Xin-Lin Chen,
| | - Xin-Lin Chen
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Fengbin Liu, ; Xin-Lin Chen,
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Pernomian L, Duarte-Silva M, de Barros Cardoso CR. The Aryl Hydrocarbon Receptor (AHR) as a Potential Target for the Control of Intestinal Inflammation: Insights from an Immune and Bacteria Sensor Receptor. Clin Rev Allergy Immunol 2021; 59:382-390. [PMID: 32279195 DOI: 10.1007/s12016-020-08789-3] [Citation(s) in RCA: 155] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The aryl hydrocarbon receptor (AHR) is widely expressed in immune and non-immune cells of the gut and its activation has been correlated to the outcome of inflammatory bowel diseases (IBD). In ulcerative colitis and Crohn's disease, there is an excessive chronic inflammation with massive accumulation of leukocytes in the gut, in an attempt to constrain the invasion of pathogenic microorganisms on the damaged organ. Accordingly, it is known that dietary components, xenobiotics, and some chemicals or metabolites can activate AHR and induce the modulation of inflammatory responses. In fact, the AHR triggering by specific ligands during inflammatory conditions results in decreased IFNγ, IL-6, IL-12, TNF, IL-7, and IL-17, along with reduced microbial translocation and fibrosis in the gut. Moreover, upon AHR activation, there are increased regulatory mechanisms such as IL-10, IL-22, prostaglandin E2, and Foxp3, besides the production of anti-microbial peptides and epithelial repair. Most interestingly, commensal bacteria or their metabolites may also activate this receptor, thus contributing to the restoration of gut normobiosis and homeostasis. In line with that, Lactobacillus reuteri, Lactobacillus bulgaricus, or microbial products such as tryptophan metabolites, indole-3-pyruvic acid, urolithin A, short-chain fatty acids, dihydroxyquinoline, and others may regulate the inflammation by mechanisms dependent on AHR activation. Hence, here we discussed the potential modulatory role of AHR on intestinal inflammation, focused on the reestablishment of homeostasis through the receptor triggering by microbial metabolites. Finally, the development of AHR-based therapies derived from bacteria products could represent an important future alternative for controlling IBD.
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Affiliation(s)
- Larissa Pernomian
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Murillo Duarte-Silva
- Department of Biochemistry and Immunology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Cristina Ribeiro de Barros Cardoso
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
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12
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Negi S, Saini S, Tandel N, Sahu K, Mishra RP, Tyagi RK. Translating Treg Therapy for Inflammatory Bowel Disease in Humanized Mice. Cells 2021; 10:1847. [PMID: 34440615 PMCID: PMC8393385 DOI: 10.3390/cells10081847] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 02/07/2023] Open
Abstract
Crohn's disease and ulcerative colitis, two major forms of inflammatory bowel disease (IBD) in humans, afflicted in genetically predisposed individuals due to dysregulated immune response directed against constituents of gut flora. The defective immune responses mounted against the regulatory mechanisms amplify and maintain the IBD-induced mucosal inflammation. Therefore, restoring the balance between inflammatory and anti-inflammatory immunepathways in the gut may contribute to halting the IBD-associated tissue-damaging immune response. Phenotypic and functional characterization of various immune-suppressive T cells (regulatory T cells; Tregs) over the last decade has been used to optimize the procedures for in vitro expansion of these cells for developing therapeutic interventional strategies. In this paper, we review the mechanisms of action and functional importance of Tregs during the pathogenesis of IBD and modulating the disease induced inflammation as well as role of mouse models including humanized mice repopulated with the human immune system (HIS) to study the IBD. "Humanized" mouse models provide new tools to analyze human Treg ontogeny, immunobiology, and therapy and the role of Tregs in developing interventional strategies against IBD. Overall, humanized mouse models replicate the human conditions and prove a viable tool to study molecular functions of human Tregs to harness their therapeutic potential.
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MESH Headings
- Adoptive Transfer
- Animals
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/therapy
- Crohn Disease/genetics
- Crohn Disease/immunology
- Crohn Disease/metabolism
- Crohn Disease/therapy
- Disease Models, Animal
- Hematopoietic Stem Cell Transplantation
- Humans
- Mice, Transgenic
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/transplantation
- Transplantation, Heterologous
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Affiliation(s)
- Sushmita Negi
- Biomedical Parasitology and Nano-Immunology Lab, Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India; (S.N.); (S.S.); (K.S.)
- BERPDC Department, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India
| | - Sheetal Saini
- Biomedical Parasitology and Nano-Immunology Lab, Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India; (S.N.); (S.S.); (K.S.)
| | - Nikunj Tandel
- Institute of Science, Nirma University, Ahmedabad, Gujarat 382481, India;
| | - Kiran Sahu
- Biomedical Parasitology and Nano-Immunology Lab, Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India; (S.N.); (S.S.); (K.S.)
| | - Ravi P.N. Mishra
- BERPDC Department, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India
| | - Rajeev K. Tyagi
- Biomedical Parasitology and Nano-Immunology Lab, Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India; (S.N.); (S.S.); (K.S.)
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Hu HF, Zhan YZ, Ding JN, Guo LY, Jin WF, Zhang XH. Clinical observation and preliminary study of mechanism of daphnetin in improving therapeutic effects for colitis. Shijie Huaren Xiaohua Zazhi 2021; 29:223-230. [DOI: 10.11569/wcjd.v29.i5.223] [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] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Daphnein is the first new drug in China. In addition to the treatment of cardiovascular diseases and coronary heart disease, daphnein also has anti-inflammatory, anti-apoptosis, analgesia, and immunity-enhancing activities. Some studies have reported that daphnetin may inhibit the activities of cyclooxygenase and 5-ester oxidase and produce anti-inflammatory and anti-allergic reactions by inhibiting the synthesis of prostaglandin and leukotriene.
AIM To explore the efficacy of daphnetin in the treatment of colitis, and observe its effect on the composition of microbiota and the balance of regulatory T cells (Treg)/helper Th17 cells (Th17).
METHODS One hundred and eight patients with ulcerative colitis (UC) admitted to our hospital from June 2017 to November 2019 were selected and randomly divided into either a control group or an observation group, with 54 cases in each group. Both groups were given conventional Western medicine treatment, and the observation group was additionally given daphnetin. The total effective rate, Baron endoscopic score, Geboes mucosal histology score, modified Mayo activity index, intestinal flora distribution, Treg/Th17 balance changes [CD4+CD25+Foxp3+ Treg, interleukin-10 (IL-10), transforming growth factor β (TGF-β), CD3+CD4+IL-17A+ Th17, interleukin-17 (IL-17), and interleukin-21 (IL-21)], the simplified Chinese version of the Inflammatory Bowel Disease Quality of Life Scale (IBDQ) score, and adverse reactions of the two groups were compared.
RESULTS The total effective rate of the observation group was 90.74%, which was higher than that of the control group (70.37%; P < 0.05). Baron endoscopy score, Geboes mucosal histology score, and modified Mayo activity index of the observation group after treatment were significantly lower than those of the control group (P < 0.05). The numbers of E. coli, Bacteroides, and Enterococcus in the observation group were significantly lower and those of Lactobacillus and Bifidobacterium were significantly higher in the observation group than in the control group (P < 0.05). CD4+CD25+Foxp3+ Treg, IL-10, and TGF-β were significantly higher and CD3+CD4+IL-17A+ Th17, IL-17, and IL-21 were significantly lower in the observation group than in the control group (P < 0.05). The scores of emotional ability, intestinal symptoms, social ability, and systemic symptoms on the IBDQ scale were significantly higher in the observation group than in the control group (P < 0.05).
CONCLUSION Daphnetin can promote the healing of the intestinal mucosa of UC patients by modulating the microbiome composition and Treg/Th17 balance and effectively improve the patient's condition and quality of life, which is safe and reliable.
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Affiliation(s)
- Hong-Feng Hu
- Department of Gastroenterology, Shaoxing Central Hospital, Shaoxing 312000, Zhejiang Province, China
| | - Ya-Zhen Zhan
- Department of Gastroenterology, Shaoxing Central Hospital, Shaoxing 312000, Zhejiang Province, China
| | - Jin-Nan Ding
- Department of Gastroenterology, Shaoxing Central Hospital, Shaoxing 312000, Zhejiang Province, China
| | - Lv-Yun Guo
- Department of Gastroenterology, Shaoxing Central Hospital, Shaoxing 312000, Zhejiang Province, China
| | - Wei-Fang Jin
- Department of Gastroenterology, Shaoxing Central Hospital, Shaoxing 312000, Zhejiang Province, China
| | - Xing-Hua Zhang
- Department of Gastroenterology, Shaoxing Central Hospital, Shaoxing 312000, Zhejiang Province, China
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14
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Abstract
Mucosal surfaces are distinctive sites exposed to environmental, dietary, and microbial antigens. Particularly in the gut, the host continuously actively adapts via complex interactions between the microbiota and dietary compounds and immune and other tissue cells. Regulatory T cells (Tregs) are critical for tuning the intestinal immune response to self- and non-self-antigens in the intestine. Its importance in intestinal homeostasis is illustrated by the onset of overt inflammation caused by deficiency in Treg generation, function, or stability in the gut. A substantial imbalance in Tregs has been observed in intestinal tissue during pathogenic conditions, when a tightly regulated and equilibrated system becomes dysregulated and leads to unimpeded and chronic immune responses. In this chapter, we compile and critically discuss the current knowledge on the key factors that promote Treg-mediated tolerance in the gut, such as those involved in intestinal Treg differentiation, specificity and suppressive function, and their immunophenotype during health and disease. We also discuss the current state of knowledge on Treg dysregulation in human intestine during pathological states such as inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), graft-versus-host disease (GVHD), and colorectal cancer (CRC), and how that knowledge is guiding development of Treg-targeted therapies to treat or prevent intestinal disorders.
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15
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Role of PD-L1 in Gut Mucosa Tolerance and Chronic Inflammation. Int J Mol Sci 2020; 21:ijms21239165. [PMID: 33271941 PMCID: PMC7730745 DOI: 10.3390/ijms21239165] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/25/2020] [Accepted: 11/27/2020] [Indexed: 12/11/2022] Open
Abstract
The gastrointestinal (GI) mucosa is among the most complex systems in the body. It has a diverse commensal microbiome challenged continuously by food and microbial components while delivering essential nutrients and defending against pathogens. For these reasons, regulatory cells and receptors are likely to play a central role in maintaining the gut mucosal homeostasis. Recent lessons from cancer immunotherapy point out the critical role of the B7 negative co-stimulator PD-L1 in mucosal homeostasis. In this review, we summarize the current knowledge supporting the critical role of PD-L1 in gastrointestinal mucosal tolerance and how abnormalities in its expression and signaling contribute to gut inflammation and cancers. Abnormal expression of PD-L1 and/or the PD-1/PD-L1 signaling pathways have been observed in the pathology of the GI tract. We also discuss the current gap in our knowledge with regards to PD-L1 signaling in the GI tract under homeostasis and pathology. Finally, we summarize the current understanding of how this pathway is currently targeted to develop novel therapeutic approaches.
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16
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Taming the Sentinels: Microbiome-Derived Metabolites and Polarization of T Cells. Int J Mol Sci 2020; 21:ijms21207740. [PMID: 33086747 PMCID: PMC7589579 DOI: 10.3390/ijms21207740] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 09/27/2020] [Accepted: 10/11/2020] [Indexed: 02/07/2023] Open
Abstract
A global increase in the prevalence of metabolic syndromes and digestive tract disorders, like food allergy or inflammatory bowel disease (IBD), has become a severe problem in the modern world. Recent decades have brought a growing body of evidence that links the gut microbiome’s complexity with host physiology. Hence, understanding the mechanistic aspects underlying the synergy between the host and its associated gut microbiome are among the most crucial questions. The functionally diversified adaptive immune system plays a central role in maintaining gut and systemic immune homeostasis. The character of the reciprocal interactions between immune components and host-dwelling microbes or microbial consortia determines the outcome of the organisms’ coexistence within the holobiont structure. It has become apparent that metabolic by-products of the microbiome constitute crucial multimodal transmitters within the host–microbiome interactome and, as such, contribute to immune homeostasis by fine-tuning of the adaptive arm of immune system. In this review, we will present recent insights and discoveries regarding the broad landscape of microbiome-derived metabolites, highlighting the role of these small compounds in the context of the balance between pro- and anti-inflammatory mechanisms orchestrated by the host T cell compartment.
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17
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Ogino H, Fukaura K, Iboshi Y, Nagamatsu Y, Okuno H, Nishioka K, Nishihara Y, Tanaka Y, Chinen T, Ihara E, Ogawa Y. Role of the IL-23-T-bet/GATA3 Axis for the Pathogenesis of Ulcerative Colitis. Inflammation 2020; 44:592-603. [PMID: 33040251 DOI: 10.1007/s10753-020-01358-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 10/02/2020] [Indexed: 11/28/2022]
Abstract
Ulcerative colitis (UC) has been considered a Th2- and Th17-related disease. However, anti-IL-12/23 p40 antibody, which blocks Th1 and Th17 cell induction and maintenance, has shown efficacy in treating UC, suggesting that UC might not be a prototypical Th2 and Th17 cell-mediated autoimmune disease. To verify how the immune responses in UC patients interact with each other, we analyzed the cytokine expression and transcription factors involved in the Th1, Th2, and Th17 responses. The mucosal expression of 19 cytokines and transcription factors related to Th1, Th2, and Th17 cells, as well as Tregs, were measured by quantitative polymerase chain reaction using endoscopic biopsy specimens from inflamed colons of UC patients. A correlation analysis between the cytokines and transcription factors was conducted. The characteristic cytokine profile in UC patients has two immune response clusters: Th17-related responses and Th1-/Th2-related responses. IL-23 showed a weaker association with Th17 cell-related cytokines and transcription factor RORC and a much stronger correlation with T-bet and GATA3. In the high-IL-23-expression group, the rate of chronic continuous type was higher and the remission rate lower than in the low-IL-23-expression group. IL-23 may be a very important cytokine for evaluating the UC disease condition, as the expression of IL-23 is associated with certain clinical characteristics of UC patients. A unique association between IL-23 and T-bet/GATA3 might play a key role in the pathogenesis of UC.
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Affiliation(s)
- Haruei Ogino
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-city, 812-8582, Japan.
| | - Keita Fukaura
- Department of Gastroenterology, Saiseikai Futsukaichi Hospital, Fukuoka, Japan
| | - Yoichiro Iboshi
- Department of Gastroenterology, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan
| | - Yousuke Nagamatsu
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-city, 812-8582, Japan
| | - Hiroaki Okuno
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-city, 812-8582, Japan.,Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Kei Nishioka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-city, 812-8582, Japan
| | - Yuichiro Nishihara
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-city, 812-8582, Japan
| | - Yoshimasa Tanaka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-city, 812-8582, Japan
| | - Takatoshi Chinen
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-city, 812-8582, Japan
| | - Eikich Ihara
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-city, 812-8582, Japan.,Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-city, 812-8582, Japan
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18
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Interplay between Cytokine Circuitry and Transcriptional Regulation Shaping Helper T Cell Pathogenicity and Plasticity in Inflammatory Bowel Disease. Int J Mol Sci 2020; 21:ijms21093379. [PMID: 32403220 PMCID: PMC7247009 DOI: 10.3390/ijms21093379] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/07/2020] [Accepted: 05/09/2020] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic disorder manifested as Crohn’s disease (CD) and ulcerative colitis (UC) characterized by intestinal inflammation and involves a dysregulated immune response against commensal microbiota through the activation of CD4 T helper cells. T helper cell differentiation to effector or regulatory phenotypes is controlled by cytokine networks and transcriptional regulators. Distinct polarized T helper cells are able to alter their phenotypes to adapt to diverse and fluctuating physiological environments. T helper cells exhibit intrinsic instability and flexibility to express cytokines of other lineages or transdifferentiate from one T helper cell type to another in response to various perturbations from physiological cytokine milieu as a means of promoting local immunity in response to injury or ensure tissue homeostasis. Furthermore, functional plasticity and diversity of T helper cells are associated with pathogenicity and are critical for immune homeostasis and prevention of autoimmunity. In this review, we provide deeper insights into the combinatorial extrinsic and intrinsic signals that control plasticity and transdifferentiation of T helper cells and also highlight the potential of exploiting the genetic reprogramming plasticity of T helper cells in the treatment of IBD.
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19
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Tindemans I, Joosse ME, Samsom JN. Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD. Cells 2020; 9:E110. [PMID: 31906479 PMCID: PMC7016883 DOI: 10.3390/cells9010110] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/20/2019] [Accepted: 12/26/2019] [Indexed: 12/12/2022] Open
Abstract
Infiltration of the lamina propria by inflammatory CD4+ T-cell populations is a key characteristic of chronic intestinal inflammation. Memory-phenotype CD4+ T-cell frequencies are increased in inflamed intestinal tissue of IBD patients compared to tissue of healthy controls and are associated with disease flares and a more complicated disease course. Therefore, a tightly controlled balance between regulatory and inflammatory CD4+ T-cell populations is crucial to prevent uncontrolled CD4+ T-cell responses and subsequent intestinal tissue damage. While at steady state, T-cells display mainly a regulatory phenotype, increased in Th1, Th2, Th9, Th17, and Th17.1 responses, and reduced Treg and Tr1 responses have all been suggested to play a role in IBD pathophysiology. However, it is highly unlikely that all these responses are altered in each individual patient. With the rapidly expanding plethora of therapeutic options to inhibit inflammatory T-cell responses and stimulate regulatory T-cell responses, a crucial need is emerging for a robust set of immunological assays to predict and monitor therapeutic success at an individual level. Consequently, it is crucial to differentiate dominant inflammatory and regulatory CD4+ T helper responses in patients and relate these to disease course and therapy response. In this review, we provide an overview of how intestinal CD4+ T-cell responses arise, discuss the main phenotypes of CD4+ T helper responses, and review how they are implicated in IBD.
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Affiliation(s)
| | | | - Janneke N. Samsom
- Laboratory of Pediatrics, Division Gastroenterology and Nutrition, Erasmus MC-Sophia Children’s Hospital, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
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20
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Wang Q, Li J, Yu TS, Liu Y, Li K, Liu S, Liu Y, Feng Q, Zhang L, Li GS, Shao LL, Peng J, Hou M, Liu XG. Disrupted balance of CD4 + T-cell subsets in bone marrow of patients with primary immune thrombocytopenia. Int J Biol Sci 2019; 15:2798-2814. [PMID: 31853219 PMCID: PMC6909963 DOI: 10.7150/ijbs.33779] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 10/05/2019] [Indexed: 12/18/2022] Open
Abstract
Disequilibrium of CD4+ T-cell subpopulations in peripheral blood (PB) of patients with primary immune thrombocytopenia (ITP) has been well established, whereas the profile of CD4+ T-cell subpopulations in bone marrow (BM) remains elusive. In the present study, the frequencies of T helper 22 (Th22), Th17, Th1, Th2, follicular T helper (Tfh) cells and regulatory T cells (Tregs) as well as their effector cytokines in BM and PB from active ITP patients and healthy controls (HCs) were determined. Results showed that the frequencies of Th22, Th17, Th1, and Tfh cells were significantly higher, but Treg number was remarkably lower in BM from ITP patients than from HCs. In the ITP group, it was notable that the numbers of BM Th22, Th17, Th1, Th2, and Tfh cells were significantly elevated compared with the matched PB counterparts, while Treg number in BM was considerably reduced compared with that in PB. In consistence with the BM Th subset pattern, plasma levels of interleukin (IL)-22, IL-17A, and interferon (INF)-γ in BM from ITP patients were significantly increased compared with that from HCs. Therefore, the balance of CD4+ T-cell subsets was disrupted in both BM and PB of ITP patients, suggesting that this might play important roles in the pathophysiological process of ITP.
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Affiliation(s)
- Qian Wang
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, P. R. China.,Department of Clinical Laboratory, Qilu Hospital, Shandong University (Qingdao), 758 Hefei Road, Qingdao, P. R. China
| | - Juan Li
- Department of Clinical Laboratory, Qilu Hospital, Shandong University (Qingdao), 758 Hefei Road, Qingdao, P. R. China
| | - Tian-Shu Yu
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, P. R. China
| | - Yu Liu
- School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, 3501 Daxue Road, Jinan, P. R. China
| | - Kai Li
- Department of Radiotherapy, Zhangqiu People's Hospital, 1920 Huiquan Road, Jinan, P. R. China
| | - Shuang Liu
- Department of Hematology, Taian Central Hospital, Taian, P. R. China
| | - Yang Liu
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, P. R. China
| | - Qi Feng
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, P. R. China
| | - Lei Zhang
- Department of Orthopedics, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Guo-Sheng Li
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, P. R. China
| | - Lin-Lin Shao
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, P. R. China
| | - Jun Peng
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, P. R. China
| | - Ming Hou
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, P. R. China.,Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan, China
| | - Xin-Guang Liu
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, P. R. China
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21
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Interleukin-17 production by CD4+CD45RO+Foxp3+ T cells in peripheral blood of patients with atherosclerosis. ACTA ACUST UNITED AC 2019; 4:e215-e224. [PMID: 31538127 PMCID: PMC6749180 DOI: 10.5114/amsad.2019.87525] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 07/08/2019] [Indexed: 12/18/2022]
Abstract
Introduction T regulatory cells (Tregs) are known as immunoregulatory cells that are reduced in atherosclerosis. Tregs are a part of crosstalk between the immune system and lipoprotein metabolism, both of which are involved in atherosclerotic processes. Depletion of Tregs leads to impaired clearance of low density lipoprotein (LDL), and intracellular cholesterol homeostasis affects Treg cell development. Furthermore, the atherosclerotic environment affects the Treg cells’ phenotype and plasticity. Plasticity between Tregs and Th17 cells has been a matter of investigation lately. We investigated the frequency of interleukin-17 (IL-17)-producing Tregs in the peripheral blood of patients with atherosclerosis. Material and methods We studied 10 non-diabetic patients with significant coronary artery disease (CAD) as the patient group, and seven non-diabetic individuals with normal coronary angiography/insignificant CAD as the control group. Peripheral blood mononuclear cells were stained with fluorescent antibodies to detect CD4, CD45RO, IL-17, and Foxp3 expression both before and after stimulation with PMA/Ionomycin. Cell enumeration was performed using flowcytometry and analysed using Mann-Whitney test. Results CD4+IL-17+Foxp3+ and CD4+IL-17+Foxp3- subsets showed higher frequencies in patients than in controls both before (p = 0.0031, p = 0.033, respectively) and after stimulation (p = 0.0027 and p = 0.0013, respectively). Interestingly, CD4+IL-17+Foxp3+ cells were almost exclusively CD45RO+ with a much higher frequency in patients than in controls (p = 0.0027, p = 0.0007). After stimulation, the frequency of CD4+CD45RO+IL-17+Foxp3+ lymphocytes increased to a greater extent in patients (p < 0.0001) than in controls. Conclusions Interleukin-17 production by an intermediate population with an activated Treg phenotype in our patients may point to the population heterogeneity or plasticity in Tregs during atherosclerotic inflammation.
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Loktionov A. Eosinophils in the gastrointestinal tract and their role in the pathogenesis of major colorectal disorders. World J Gastroenterol 2019; 25:3503-3526. [PMID: 31367153 PMCID: PMC6658389 DOI: 10.3748/wjg.v25.i27.3503] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/22/2019] [Accepted: 05/31/2019] [Indexed: 02/06/2023] Open
Abstract
Eosinophils are currently regarded as versatile mobile cells controlling and regulating multiple biological pathways and responses in health and disease. These cells store in their specific granules numerous biologically active substances (cytotoxic cationic proteins, cytokines, growth factors, chemokines, enzymes) ready for rapid release. The human gut is the main destination of eosinophils that are produced and matured in the bone marrow and then transferred to target tissues through the circulation. In health the most important functions of gut-residing eosinophils comprise their participation in the maintenance of the protective mucosal barrier and interactions with other immune cells in providing immunity to microbiota of the gut lumen. Eosinophils are closely involved in the development of inflammatory bowel disease (IBD), when their cytotoxic granule proteins cause damage to host tissues. However, their roles in Crohn's disease and ulcerative colitis appear to follow different immune response patterns. Eosinophils in IBD are especially important in altering the structure and protective functions of the mucosal barrier and modulating massive neutrophil influx to the lamina propria followed by transepithelial migration to colorectal mucus. IBD-associated inflammatory process involving eosinophils then appears to expand to the mucus overlaying the internal gut surface. The author hypothesises that immune responses within colorectal mucus as well as ETosis exerted by both neutrophils and eosinophils on the both sides of the colonic epithelial barrier act as additional pathogenetic factors in IBD. Literature analysis also shows an association between elevated eosinophil levels and better colorectal cancer (CRC) prognosis, but mechanisms behind this effect remain to be elucidated. In conclusion, the author emphasises the importance of investigating colorectal mucus in IBD and CRC patients as a previously unexplored milieu of disease-related inflammatory responses.
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Yan SC, Wang YJ, Li YJ, Cai WY, Weng XG, Li Q, Chen Y, Yang Q, Zhu XX. Dihydroartemisinin Regulates the Th/Treg Balance by Inducing Activated CD4+ T cell Apoptosis via Heme Oxygenase-1 Induction in Mouse Models of Inflammatory Bowel Disease. Molecules 2019; 24:molecules24132475. [PMID: 31284478 PMCID: PMC6651826 DOI: 10.3390/molecules24132475] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 06/19/2019] [Accepted: 07/04/2019] [Indexed: 12/13/2022] Open
Abstract
Dihydroartemisinin (DHA) is a derivative of the herb Artemisia annua L. that has prominent immunomodulatory activity; however, its underlying mechanism remains elusive. Inflammatory bowel disease (IBD) is an idiopathic inflammatory condition characterized as an autoimmune disorder that includes dysfunctions in the T helper (Th)/T regulatory cell (Treg) balance, which normally plays pivotal roles in immune homeostasis. The aim of this study was to explore the potential of DHA to ameliorate IBD by restoring the Th/Treg cell balance. To this end, we established mouse models of colitis induced by oxazolone (OXA) and 2,4,6-trinitro-benzene sulfonic acid (TNBS). We then treated mice with DHA at 4, 8, or 16 mg/kg/day. DHA treatment ameliorated colitis signs and reduced lymphocyte infiltration and tissue fibrosis. Moreover, DHA decreased the numbers of Th1 and Th17 cells and Th9 and Th22 cells in TNBS- or OXA-induced colitis, respectively, and increased Tregs in both models. DHA (0.8 mg/mL) also inhibited activated CD4+ T lymphocytes, which was accompanied by apoptosis induction. Moreover, it promoted heme oxygenase-1 (HO-1) production in vitro and in vivo, concomitant with CD4+ T cell apoptosis and restoration of the Th/Treg balance, and these effects were blocked by treatment with the HO-1 inhibitor Sn-protoporphyrin IX. Overall, these results suggest that DHA is a novel and valuable candidate for IBD therapy or Th/Treg immunoregulation.
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Affiliation(s)
- Si Chao Yan
- Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Ya Jie Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yu Jie Li
- Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Wei Yan Cai
- Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Xiao Gang Weng
- Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Qi Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Ying Chen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Qing Yang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Xiao Xin Zhu
- Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China.
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
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Gui X, Li J, Ueno A, Iacucci M, Qian J, Ghosh S. Histopathological Features of Inflammatory Bowel Disease are Associated With Different CD4+ T Cell Subsets in Colonic Mucosal Lamina Propria. J Crohns Colitis 2018; 12:1448-1458. [PMID: 30137280 DOI: 10.1093/ecco-jcc/jjy116] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Inflammatory bowel disease [IBD] results particularly from an aberrance of CD4+ helper and regulatory T cells and comprises histopathologically chronic active enterocolitis with features reflecting both activity and chronicity of mucosal inflammation. The exact immunological-histological correlation in IBD is not understood. METHODS We studied the correlation between colonic mucosal CD4+ T cell subsets [Th1, Th2, Th17, Th22 and Treg] and mucosal histological changes in ulcerative colitis [UC] and Crohn's disease [CD]. CD4+ T cell subtyping and enumeration were achieved by flow cytometry. Histological features were categorized and assessed semi-quantitatively using three validated histological scoring schemes [ECAP, RHI and D'Haens]. Correlations between prevalence [%] of CD4+ T cell subsets and histological scores were analysed. RESULTS Treg cells were correlated with ECAP category A [activity] as well as RHI scores. Treg cell were increased particularly in mucosa with severe neutrophilic infiltration in the cryptal/surface epithelium and in lamina propria, and with basal plasmacytosis. Th17 cells were also increased in cases with extensive neutrophil infiltrate in lamina propria, whereas RORc+ cells were increased in cases with severe lymphoplasmacytic infiltration in lamina propria. In both UC and CD, mucosa with marked crypt architectural alteration had increased IL-22+ and Th22 cells. UC with Paneth cell metaplasia had higher Th17 cells. CD with granuloma had increased IL-22+ and IL-22+IFN-γ+ cells. CONCLUSIONS The Treg subset appears to be associated with the overall severity of IBD histopathology, particularly with active inflammation. Th17 is also associated with activity. By contrast, IL-22+ cells are associated with chronicity and granuloma formation in CD.
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Affiliation(s)
- Xianyong Gui
- Department of Pathology and Laboratory Medicine, University of Calgary, and Calgary Laboratory Services, Calgary, Alberta, Canada
| | - Ji Li
- Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.,Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China
| | - Aito Ueno
- Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada
| | - Marietta Iacucci
- Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.,Institute of Translational Medicine, University of Birmingham, Birmingham, UK
| | - Jiaming Qian
- Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China
| | - Subrata Ghosh
- Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.,Institute of Translational Medicine, University of Birmingham, Birmingham, UK
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25
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Catalan-Serra I, Andreu-Ballester JC, Bruland T, Sandvik AK. Gammadelta T Cells: Unconventional T Cells Involved in IBD Pathogenesis. Dig Dis Sci 2018; 63:1977-1979. [PMID: 29752622 DOI: 10.1007/s10620-018-5059-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 04/05/2018] [Indexed: 01/20/2023]
Affiliation(s)
- Ignacio Catalan-Serra
- Department of Medicine, Gastroenterology, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway. .,Department of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research (CEMIR), Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
| | | | - Torunn Bruland
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Clinic of Medicine, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Arne Kristian Sandvik
- Department of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research (CEMIR), Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Gastroenterology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
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26
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Guo HX, Ye N, Yan P, Qiu MY, Zhang J, Shen ZG, He HY, Tian ZQ, Li HL, Li JT. Sodium chloride exacerbates dextran sulfate sodium-induced colitis by tuning proinflammatory and antiinflammatory lamina propria mononuclear cells through p38/MAPK pathway in mice. World J Gastroenterol 2018; 24:1779-1794. [PMID: 29713131 PMCID: PMC5922996 DOI: 10.3748/wjg.v24.i16.1779] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/11/2018] [Accepted: 03/18/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the influence of high salt on dextran sulfate sodium (DSS)-induced colitis in mice and explore the underlying mechanisms of this effect. METHODS DSS and NaCl were used to establish the proinflammatory animal model. We evaluated the colitis severity. Flow cytometry was employed for detecting the frequencies of Th1, macrophages and Tregs in spleen, mesenteric lymph node and lamina propria. The important role of macrophages in the promotion of DSS-induced colitis by NaCl was evaluated by depleting macrophages with clodronate liposomes. Activated peritoneal macrophages and lamina propria mononuclear cells (LPMCs) were stimulated with NaCl, and proteins were detected by western blotting. Cytokines and inflammation genes were analyzed by enzyme-linked immunosorbent assay and RT-PCR, respectively. RESULTS The study findings indicate that NaCl up-regulates the frequencies of CD11b+ macrophages and CD4+IFN-γ+IL-17+ T cells in lamina propria in DSS-treated mice. CD3+CD4+CD25+Foxp3+ T cells, which can secrete high levels of IL-10 and TGF-β, increase through feedback in NaCl- and DSS-treated mice. Furthermore, clodronate liposomes pretreatment significantly alleviated DSS-induced colitis, indicating that macrophages play a vital role in NaCl proinflammatory activity. NaCl aggravates peritoneal macrophage inflammation by promoting the expressions of interleukin (IL)-1, IL-6 and mouse inducible nitric oxide synthase. Specifically, high NaCl concentrations promote p38 phosphorylation in lipopolysaccharide- and IFN-γ-activated LPMCs mediated by SGK1. CONCLUSION Proinflammatory macrophages may play an essential role in the onset and development of NaCl-promoted inflammation in DSS-induced colitis. The underlining mechanism involves up-regulation of the p38/MAPK axis.
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Affiliation(s)
- Hong-Xia Guo
- Department of Microbiology, Third Military Medical University (Army Medical University), District Shapingba, Chongqing 400038, China
- Institute of Tropical Medicine, Third Military Medical University (Army Medical University), District Shapingba, Chongqing 400038, China
| | - Nan Ye
- Institute of Tropical Medicine, Third Military Medical University (Army Medical University), District Shapingba, Chongqing 400038, China
| | - Ping Yan
- Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Min-Yue Qiu
- Institute of Tropical Medicine, Third Military Medical University (Army Medical University), District Shapingba, Chongqing 400038, China
| | - Ji Zhang
- Institute of Immunology, Third Military Medical University (Army Medical University), District Shapingba, Chongqing 400038, China
| | - Zi-Gang Shen
- Institute of Immunology, Third Military Medical University (Army Medical University), District Shapingba, Chongqing 400038, China
| | - Hai-Yang He
- Institute of Immunology, Third Military Medical University (Army Medical University), District Shapingba, Chongqing 400038, China
| | - Zhi-Qiang Tian
- Institute of Immunology, Third Military Medical University (Army Medical University), District Shapingba, Chongqing 400038, China
| | - Hong-Li Li
- Department of Histology and Embryology, College of Basic Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jin-Tao Li
- Department of Microbiology, Third Military Medical University (Army Medical University), District Shapingba, Chongqing 400038, China
- Institute of Tropical Medicine, Third Military Medical University (Army Medical University), District Shapingba, Chongqing 400038, China
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27
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Ueno A, Jeffery L, Kobayashi T, Hibi T, Ghosh S, Jijon H. Th17 plasticity and its relevance to inflammatory bowel disease. J Autoimmun 2018; 87:38-49. [DOI: 10.1016/j.jaut.2017.12.004] [Citation(s) in RCA: 210] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 12/03/2017] [Indexed: 02/08/2023]
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Affiliation(s)
- Elisa K Boden
- Virginia Mason Medical Center, 1100 Ninth Ave., Mailstop C3-GAS, Seattle, WA, 98101, USA
| | - James D Lord
- Virginia Mason Medical Center, 1100 Ninth Ave., Mailstop C3-GAS, Seattle, WA, 98101, USA. .,Benaroya Research Institute, 1201 Ninth Ave., Mailstop IN-RC, Seattle, WA, 98101, USA.
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